James P. Allison, Ph.D.
Professor and Chair, Department of Immunology
Vivian L. Smith Distinguished Chair in Immunology
Director, Parker Institute for Cancer Research
Executive Director, Immunotherapy Platform at MD Anderson Cancer Center
Awarded Nobel Prize in Physiology or Medicine in 2018
Dr. Allison received his Ph.D. from the University of Texas at Austin (Austin, TX) and completed a postdoctoral fellowship at Scripps Clinical and Research Foundation in the Department of Molecular Immunology (La Jolla, CA). Dr. James Allison is the Chair of the Department of Immunology, the Vivian L. Smith Distinguished Chair in Immunology, Director of the Parker Institute for Cancer Research, and the Executive Director of the Immunotherapy Platform at MD Anderson Cancer Center. He has spent a distinguished career studying the regulation of T cell responses and developing strategies for cancer immunotherapy. Among his most notable discoveries are the determination of the T cell receptor structure and that CD28 is the major costimulatory molecule that allows full activation of naïve T cells and prevents anergy in T cell clones. His lab resolved a major controversy by demonstrating that CTLA-4 inhibits T-cell activation by opposing CD28-mediated costimulation and that blockade of CTLA-4 could enhance T cell responses, leading to tumor rejection in animal models. This finding paved the wave for the emerging field of immune checkpoint blockade therapy for cancer. Work in his lab led to the development of ipilimumab, an antibody to human CTLA-4 and the first immune checkpoint blockade therapy approved by the FDA. Dr. Allison is one of the world’s most renowned scientists. Among many honors, he is a member of the National Academies of Science and Medicine and received the Lasker-Debakey Clinical Medical Research award in 2015. His current work seeks to improve immune checkpoint blockade therapies currently used by our clinicians and identify new targets to unleash the immune system in order to eradicate cancer.
Allison Laboratory Research:
The Allison laboratory is interested in murine models of tumor immunotherapy, T-cell activation and regulation, and the development of immunotherapy strategies for cancer.
Dr. Andreeff received his M.D. and Ph.D. degrees at the University of Heidelberg, Germany, and additional training and faculty appointments at the Memorial Sloan-Kettering Cancer Center (MSKCC) in New York, NY, in the Departments of Pathology and Leukemia.
Dr. Andreeff has been a pioneer in flow cytometry since 1971, when he established the first flow cytometry laboratory at the University of Heidelberg, and organized the first European conference on flow cytometry. In 1977 he joined Memorial Sloan-Kettering Cancer Center in New York, NY, became head of the Leukemia Cell Biology and Hematopathology flow cytometry laboratory, organized the first Clinical Cytometry Conference in 1986 and the first Molecular Cytogenetics Conference in 1990.
He is professor of medicine and holds the Paul and Mary Haas Chair in Genetics at MD Anderson. He has received uninterrupted NCI funding for over 30 years, serves as PI of the P01 grant entitled “The Therapy of AML”, participates as PI in MD Anderson Leukemia, Lymphoma, Ovarian and Breast Cancer SPORE grants, the CML P01 and additional R21 and R01 grants. He has published over 450 peer-reviewed papers, 5 books and 75 book chapters.
Andreeff Laboratory Research:
Molecular Hematology and Therapy is a Section in the Leukemia Department with close links to the Department of Stem Cell Transplantation and Cellular Therapy. Our focus is on leukemia research, with emphasis on apoptosis regulation, signaling pathways (FLT3-Ras-Ras-MEK-ERK, PI3K-AKT-mTOR, STAT3 and 5) , their links to apoptosis and autophagy and to the micro-environment. The Section encompasses 12 faculty and 25 additional scientists and includes the MD Anderson CCSG-sponsored "Flow Cytometry/Cell Sorting/Confocal Microscopy" Core Lab. Investigations of apoptosis and cell signaling pathways resulted in the development of new drug targets including Bcl-2, BclXL, McL-1, MDM2/p53, inhibitors-of-apoptosis proteins (XIAP, Survivin, cIAP1,2), FLT3-ITD, AKT/mTOR and pERK, which we have moved from basic to translational research into trials. We emphasize that successful drug development has to target the right cells ("primary stem cells", not cell line cells) in the physiological, i.e. hypoxic tumor microenvironment. Our group has major expertise in the study of hematopoietic and solid tumor systems . We were first to report the critical role of bone marrow-derived MSC (mesenchymal stem cells) in the formation of tumor stroma and have developed therapies that deliver therapeutic genes into tumors by way of MSC. Several transgenic and knock-out mouse models have been developed to provide a better understanding of tumor- and microenvironmental molecular biology. Leukemia cells with most relevant translocations and mutations have been generated in collaboration with CSH. Major efforts are ongoing to disrupt interactions between leukemia/tumor stem cells and their micro-environment (targeting CXCR4, VLA-4, CD44). The first fully human system forming bone and bone marrow has been developed in immuno-deficient NOG mice, whose components can be genetically modified. Finally, in collaborations with pharmaceutical corporations and biotechnology companies, drugs are being developed targeting genes, RNAs and proteins of interest.
Dr. Arur obtained her Ph.D. with Prof. M.K. Bhan from the All India Institute of Medical Sciences. Dr. Arur undertook post-graduate studies with Dr. David Han, at the UCONN Health Science Center where she spearheaded one of the earliest efforts in deploying state-of-the-art differential proteomics technology (LC-MS/MS coupled with ICAT) to understand how dying cells were cleared by phagocytes. Subsequently, Dr. Arur received a postdoctoral fellowship from the Washington University School of Medicine in St. Louis to train in the laboratory of Prof. Tim Schedl.
In 2010, Dr. Arur established her laboratory in the Department of Genetics. Her lab uses multidisciplinary approaches and model systems with the goal to gain knowledge and understanding on principles that regulate female fertility and onset and progression of metastatic KRAS driven cancers. These studies will enable fundamental mechanistic understanding of developmental disorders and oncogenesis. Dr. Arur is a Research Scholar of the American Cancer Society, Anna Fuller Foundation, and Andrew Sabin Family Foundation. Her laboratory is currently funded by the National Institute of Health, Cancer Prevention and Research Institute of Texas and American Cancer Society.
The Arur laboratory uses multidisciplinary approaches and model systems with the goal to gain knowledge and understanding on principles that regulate female fertility. We focus on meiosis I, which is largely completed in the female fetus in vertebrates. Specifically, we focus on the role of maternal environment and nutrition on progression of female meiosis I, and its impact on birth and development of the progeny.
Female germ cell development
· Nutritional and environmental signals that coordinate female fertility
· Mechanisms of cancer progression and metastasis
Dr. Bankson leads the Magnetic Resonance Engineering Laboratory at The University of Texas MD Anderson Cancer Center, and he is Deputy Director of the Small Animal Imaging Facility. His research is focused on the use of engineering principles (RF engineering, systems engineering, electromagnetics, signal and image processing) to refine, optimize, and extend methods to characterize disease non-invasively using magnetic resonance imaging, spectroscopy, and spectroscopic imaging.
The mission of the Magnetic Resonance Systems Laboratory (MSRL) is to develop new imaging technologies that improve our ability to measure and understand cancer and response to therapy. We apply expertise in engineering and physics in a highly interdisciplinary environment to engage the problem of cancer from the test tube to the clinic.
We aim to enable scientists and clinicians with new tools to characterize cancer with unprecedented resolution, ultimately to improve outcome and quality of life for patients affected by cancer.
· To develop robust and reproducible methods for metabolic imaging hyperpolarized substrates
· To characterize and refine strategies that derive more information from less data
· To develop new instrumentation that lowers the price barrier for imaging in biomedical research
· To develop new methods to visualize disease, therapy and response to therapy
· To characterize, refine, and use quantitative imaging biomarkers to understand disease and response to therapy
· To ensure that imaging capabilities advance in step with next-generation therapeutics to maximize efficacy and ensure rapid clinical translation
Robert C. Bast, Jr., M.D.
Professor, Department of Translational Research
Harry Carothers Wiess Distinguished University Chair for Cancer Research
Vice President for Translational Research
Internist and Professor of Medicine, Department of Experimental Therapeutics
Dr. Bast received his M.D. at Harvard Medical School (Boston, MA) and completed postgraduate training and research at several notable institutions including Massachusetts General Hospital, Johns Hopkins Hospital, the National Cancer Institute, Harvard Medical School, Peter Bent Brigham Hospital, and Sydney Farber Cancer Institute. He is the recipient of numerous recognitions and awards.
Bast Laboratory Research:
Our laboratory is addressing three of the critical problems in the management of ovarian cancer, including late detection, drug resistance and tumor dormancy, while attempting to understand the heterogeneity of ovarian cancers at a cellular and molecular level. Projects in which fellows would be welcomed include:
1) Function of imprinted tumor suppressor genes that are downregulated in ovarian cancer. Over the last decade, we have identified several imprinted tumor suppressor genes whose expression is decreased or lost in ovarian cancer. Among these, we have best characterized ARHI (DIRAS3) which encodes a 26kD GTPase with 50% homology to Ras, but with an opposite function that can be attributed to a 34 amino acid N terminal extension. ARHI is downregulated in 60% of ovarian cancers associated with decreased disease free survival. Expression from the single functioning allele can be inhibited by LOH, hypermethylation or transcriptional regulation by E2F1 or E2F4 in different cancers. Re-expression of ARHI inhibits proliferation and motility while inducing autophagy and tumor dormancy. Current studies, funded by an R01, concern mechanisms underlying ARHI-induced autophagy and requirements for survival of dormant ovarian cancer cells. For these studies, we have developed the first inducible model for tumor dormancy in ovarian cancer.
2) Individualized enhancement of primary sensitivity to paclitaxel in different ovarian cancers. Through a high throughput kinome siRNA screen, my laboratory has identified more than 30 kinases that regulate paclitaxel sensitivity in ovarian cancer cell lines by modulating centrosome function (SIK2), paclitaxel retention (CDK5) or microtubule stability (ILK, FER). Both fundamental studies of mechanism and translational studies of siRNA therapy in combination with paclitaxel are being pursued.
3) Identification of biomarkers and strategies for early detection of ovarian cancer. Having developed the CA125 serum assay for monitoring ovarian cancer, we have tested some 115 potential biomarkers to identify four biomarker panels for early stage disease. Currently, we are testing several such panels for their ability to discriminate women with pre-clinical and early stage disease from healthy women. Supported by an Ovarian SPORE, a multi-year screening trial is being conducted in 3000 apparently healthy postmenopausal women to evaluate the specificity and positive predictive value of ultrasound in a small fraction of women with rising levels of biomarkers from year to year. To date, the trial has prompted 8 operations to discover 5 cases of ovarian cancer, all in early stage, consistent with a positive predictive value of 37%, i.e. only 3 operations per case of ovarian cancer detected. To facilitate these studies, we are collaborating with investigators at Rice to place assays on nanobiochips for testing at point of service. Recent work with protein expression arrays has identified a panel of 115 auto antibodies which promise to detect pre-clinical disease in a larger fraction of women.
The focus of my research is the early detection and prevention of liver cancer. Liver cancer is the third cause of cancer-related mortality worldwide and its incidence is significantly increasing in the United States. There are three main components in my lab’s research activities.
Mechanisms of hepatocarcinogenesis: Using mouse models of liver cancer that mimic the human disease and exhibit progression from liver fibrosis and steatohepatitis to tumor development, my lab has characterized hepatic and plasma protein changes that occur during this disease process. We are currently focusing on specific networks that encompass the tumor microenvironment and lipid metabolism, to test novel hypotheses related to tumor development and progression. We are also investigating the role liver progenitor cells may play in liver tumor initiation in cirrhotic livers. We have characterized the molecular events (at the mRNA, protein and microRNA levels) that occur during hepatocytic differentiation of liver progenitor cells and are evaluating the consequences of their dysregulation on tumor initiation.
Novel strategies for early detection of hepatocellular carcinoma (HCC): We have identified novel potential markers for early detection of hepatocellular carcinoma among subjects at risk. We are now focusing on their validation. We have to date reported that osteopontin has higher performance than the current diagnostic marker AFP for discriminating between subjects with liver cirrhosis and patients with HCC, up to one year prior to a diagnosis of HCC. We are currently validating additional markers. For this project, we established an extensive network of subject cohorts nationally and internationally (China, France, Korea, Thailand, The Gambia) including prospective cohorts of patients at risk for liver cancer. These cohorts represent an important resource for biomarker validation.
• Mammalian developmental genetics • Reproductive biology • Evolution and development
Our research focuses on the molecular and cellular mechanisms that lead to the formation of a mammalian embryo, the genesis of tissues and organs during development, and the pathological consequences of developmental defects. In addition, we study the genetic mechanisms that result in organ morphology and physiology differences that have evolved between species. We utilize genetic, embryological and comparative approaches.
The reproductive organs are essential for individuals to generate progeny and are a common source of disease. We are interested in defining the factors that cause the male and female phenotypes, including gonad and reproductive tract differentiation during embryogenesis and after birth. We are currently defining gene regulatory networks for reproductive organ development, using "-omics" profiling of developing reproductive organ tissues and generation of mutations in a variety of vertebrate species, including mammals, amphibians, reptiles, and birds.
We are also investigating developmental processes in diverse mammalian systems, including marsupials and chiropterans (bats). Mammalian embryogenesis and reproduction are very diverse between species, comparisons provide novel insights for reproduction, embryonic development and organogenesis. We collaborate with Marilyn Renfree (University of Melbourne) using the tammar wallaby (Macropus eugenii) model to study sexual
differentiation and limb development. Bats also offer a unique system to study the genetic mechanisms that diversify organogenesis. We have collaborated with John Rasweiler to establish the molecular embryology of the fruit bat, Carollia perspicillata. Our wallaby and bat studies are supported by field collections on Kangaroo Island, Australia and the island of Trinidad, respectively. In addition, we have a frozen archive of fibroblasts from >250 mammalian species previously collected by Drs. Tao-Chiuh (T.C.) Hsu and Sen Pathak. This "cryo zoo" serves as a rich source of genetic and cellular
The focus of research in Dr. Bhattacharya's laboratory in the Department of Cancer Systems Imaging is the development of real-time metabolic and imaging applications by hyperpolarization. We are exploring novel ways to utilize Magnetic Resonance Imaging (MRI) to create more detailed metabolic and molecular imaging studies by employing hyperpolarized, non-radioactive carbon 13 (13C) and nitrogen 15 (15N)-labeled compounds and silicon particles and nanoparticles (SiNPs) to tag specific metabolic and biochemical structures and functions that are altered in cancer. Hyperpolarized MR is a non-toxic, non-radioactive method for non-invasively assessing tissue metabolism and other physiologic properties. Hyperpolarization allows for a >10,000-fold signal enhancement relative to conventional MRI or MRS. After hyperpolarization, the signal enhancement can be retained on the metabolites of the hyperpolarized molecules for several minutes. Dr. Bhattacharya’s, lab is working on techniques to extend this relaxation time so that more detailed metabolic and molecular imaging studies can be considered.
The Magnetic Resonance laboratory is involved in three primary areas of research:
·Real time metabolic MR imaging with hyperpolarized 13C and 15N labeled non-radioactive compounds. The goal of this research is to use mostly
endogenous compounds to track different metabolic pathways in vivo in real time both in preclinical animal models and in human applications.
·Real-time molecular MR imaging with hyperpolarized silicon nanoparticle (SiNPs) functionalized to target specific biological functions and structure.
Hyperpolarized SiNPs have opened the door for targeted functional imaging by MR that used to be in the realm of PET and SPECT. Due to the simple surface chemistry, the hyperpolarized SiNPs can serve as a nanoplatform, allowing a variety of targeting agents and potentially therapeutic drugs to be loaded onto the particles, which enables real-time targeted Theranostics imaging studies with an imaging time window of roughly one hour.
·High resolution MR metabolomics of animal and human tissues. To complement the real-time in vivo hyperpolarization studies, we have developed an MR based metabolomics program to generate comprehensive metabolic profiles of cancerous and non-cancerous tissues in vitro.
Over the past eight years, my laboratory has worked on the development of different modalities of hyperpolarization like Parahydrogen Induced Polarization (PHIP), Dynamic Nuclear Polarization (DNP), Continuous Flow DNP of water and solid-state DNP processes of Silicon nanoparticles as well as developed applications in various types of cancer, cardiovascular diseases and tobacco-related diseases. My laboratory has developed hyperpolarized imaging probes like succinic acid, diethyl succinate and tetrafluoropropylprionate (TFPP) that can interrogate metabolic pathways in real time in vivo as well act as molecular imaging probes of atherosclerotic plaque in rodent models. I enjoy close collaboration with physician/scientists, radiologists, oncologists, and basic cancer researchers to explore new opportunities and identify critical needs to ensure that imaging science advances alongside novel therapeutic approaches to improve the next generation of clinical care.
I have a primary research interest in the interaction of human modeling and radiation therapy. I have investigated the ability of biomechanical models to
enhance the veracity of human deformable modeling and have evaluated the accuracy of deformable alignment methods applied to radiation oncology problems such as contour propagation and dose accumulation. I developed MORFEUS, a comprehensive system for deformable modeling, and lead several investigations in its use on radiation therapy, correlative pathology, and other areas of interest. Over the past few years, I have expanded the biomechanical models to describe anatomical response to radiation, including volume changes and position within the human body.
Imaging is a critical component in the detection, characterization and treatment of cancer. The rich information content of advanced imaging methods, combined with the growing capacity to collect multiple types of images from various sources and time points during therapy opens an exciting prospect for image-based guidance and assessment of interventions for radiation oncology, surgery, interventional radiology and image-guided drug delivery. However, a major obstacle to full exploitation of this paradigm is the natural deformations in anatomy between imaging events or between imaging and intervention events.
It is my vision that mechanically informed models of human anatomy can regularize these variations and allow maximum information extraction from these data sources. Failure to develop tools to address this will limit both the discovery of new information from these sources as well as the application of this information in patient treatment.
Dr. Brown earned his Ph.D. in Immunology and M.D. from New York University.
Brown Laboratory Research:
In my laboratory, we focus on identifying molecules that are necessary for the growth, survival, and transformation of breast cancers. We work to identifying the critical molecular pathways that control breast cell growth, transformation, progression, and metastasis, and then target these molecular pathways to treat and prevent the most aggressive forms of breast cancer. For this research we employ an integrated whole-genome approach with RNA (mRNA, miRNA, and lncRNA), DNA, proteomic, and epigenomic analyses to identify novel and critical molecular pathways in breast cancer cells. We are currently:
- Identifying critical signaling molecules using innovative screens (synthetic lethality screens, small molecule screens, siRNA/sgRNA screens)
- Investigating the functions of specific critical signaling molecules (kinases, phosphatases, and cytokines) in regulating breast cell growth, death, invasion, and metastasis
- Developing strategies to target these signaling molecules (using small molecule drugs, liposomal siRNAs, dominant-negative genes) that are capable of blocking or interfering with transformation and cell growth
- Testing the activity of the molecular inhibitors in human clinical trials
We use a wide range of techniques to conduct this research, including bioinformatic and computation biology, whole genome screening methods, molecular biology studies of gene expression, cellular biological studies of normal, premalignant, and fully cancerous human breast cells, studies of human breast samples, and in vivo animal studies using molecular inhibitors in transgenic and knockout mice. We also routinely use systems biology, bioinformatics and high-throughput screening techniques to identify novel signal transduction pathways, which then are targeted to develop new cancer therapies. Through these studies we seek to identify new strategies to treat and prevent breast cancer.
Dr. Byers completed her B.A. degree in Molecular Biology at Princeton University in 1998, her M.D. degree at Baylor College of Medicine in 2003, and M.S. degree in Patient-Based Research at the University of Texas Graduate School of Biomedical Sciences in 2009. Following her Clinical Residency in Internal Medicine at Johns Hopkins, Dr. Byers joined MD Anderson Cancer Center in 2006 as a Clinical Fellow in Medical Oncology and later as an Advanced Scholar Fellow. During her fellowship, Dr. Byers focused on studying gene and protein profiles of tumor samples obtained from lung cancer patients. Her work revealed major differences in the cellular pathways in small cell lung cancer (SCLC) as compared to non-small cell lung cancer (NSCLC), leading to the identification of the protein PARP1 as a novel therapeutic target for small cell lung cancer. In 2010, Dr. Byers was appointed as an Assistant Professor in the Department of Thoracic/Head and Neck Medical Oncology, and was subsequently promoted to Associate Professor in 2017. She has an impressive list of funded grants and awards, including Women Leading the Way and NCI Cancer Clinical Investigator Team Leadership Award (both in 2013), R. Lee Clark Fellow Award and President’s Recognition for Faculty Excellence (both in 2014), ASCO Top Ten Clinical Research Achievement Award (2015), and an NIH R01 (2016).
Byers Laboratory Research:
Research in the Byers Laboratory is dedicated to understanding the causes of resistance to treatment in patients diagnosed with thoracic cancers and identifying novel therapeutic targets for these diseases. The lab employs high-throughput profiling techniques to identify candidate predictive biomarkers and potential new therapeutic targets in lung cancers. Specific markers of interest which are being further investigated as therapeutic targets include the DNA damage response (DDR)proteins PARP1, WEE1, and CHK1 in small cell lung cancer and the tyrosine kinase receptor Axl in non-small cell lung cancer. Previously, they demonstrated that the Axl is a marker that can predict which patients will be resistant to treatment with EGFR inhibitors, a discovery that led to Dr. Byers initiating a clinical trial using new drug combinations to target Axl in patients resistant to therapies involving EGFR inhibitors. In addition, Dr. Byers is currently leading several clinical trials testing DDR inhibitors alone and in combination with chemotherapy for patients with recurrent small cell lung cancer.
George A. Calin received both his M.D. and Ph.D. degrees at Carol Davila University of Medicine in Bucharest, Romania. After working cytogenetics as undergraduate student with Dr. Dragos Stefanescu in Bucharest, he completed a cancer genomics training in Dr. Massimo Negrini’s laboratory at University of Ferrara, Italy. In 2000 he became a postdoctoral fellow at Kimmel Cancer Center in Philadelphia, PA. Here, he worked in Dr. Carlo Croce's laboratory and was the first to discover the link between microRNAs and human cancers, a finding considered as a milestone in microRNA research history. He is presently a Professor in Experimental Therapeutics and Leukemia Departments at MD Anderson Cancer Center in Houston and studies the roles of microRNAs and other non-coding RNAs in cancer initiation and progression and in immune disorders, as well as the mechanisms of cancer predisposition linked to non-coding RNAs. Furthermore, he explores the roles of body fluids miRNAs as potential hormones and biomarkers, as well as new RNA therapeutic options for cancer patients. Simply, he is having fun making discoveries and publishing and, from time to time, getting funded grants!
Calin Laboratory Research:
My long-term goal is to establish the roles of non-coding RNAs in human diseases. My main research interests are: 1) the involvement of non-coding RNAs in human diseases in general and of microRNAs in human cancers in particular, 2) the study of familial predisposition to human cancers, 3) the identification of ncRNA biomarkers in body fluids, and 4) the development of new RNA-based therapeutic options for cancer patients. Current areas of research in my laboratory are:
1) Identification of the Roles of microRNAs and Other Non-Coding RNAs in Cancer PredispositionFamilial cancers represent diseases in which non-coding RNAs have central pathogenetic roles. We hypothesize that previously non-identified, non-coding RNAs with roles in sporadic and familial cancers could be identified by using their genomic association (flagging) with known cancer-associated, single-nucleotide polymorphisms (SNPs). Furthermore, SNPs in interactor sites with microRNAs are involved in cancer predisposition. The genome-wide identification of non-coding RNAs predisposed to cancer would prove a new mechanism of cancer predisposition with clear implications for further molecular screening and diagnosis.
2) Identification of Non-Coding RNAs Involved in Metastasis During tumorigenesis, genome-wide abnormalities in both microRNAs and ultra-conserved genes (UCGs) occur in a correlated way that results in our hypothesis that dramatic differences occur in the expression of UCGs and miRNAs in non-metastatic versus metastatic cancers. microRNAs have important genes as targets – including known oncogenes and tumor suppressors involved in pancreatic invasion and metastasis. Additionally, miRNAs interact directly with and regulate the expression of UCGs and/or, conversely, UCGs can regulate the expression of miRNAs. The transcriptional or post-transcriptional down-regulation of target levels by miRNAs and UCGs may have functional consequences by impairing the cell cycle and the survival, migration and invasion capacity of cancer cells.
3) Identification of microRNAs and Other Non-Coding RNAs as Diagnostic and Prognostic Markers in Human Cancers microRNAs as the Oldest Hormones MicroRNA levels in the plasma from cancer patients are significantly different than those of non-cancer control individuals. The plasma miRNAs levels from cancer patients correlate with clinical and prognostic parameters and the miRNA quantification from plasma could be included as a new prognostic marker. Furthermore, the identification of traces of specific miRNAs, known to have a pathogenetic effect, could signal the recurrence of disease. Human-specific ncRNAs exist in the genome and are involved in the functional fingerprints that differentiate human cancers from cancers in other organisms. microRNAs are secreted by malignant cells in the microenvironment and uptake directly or through bodily fluids by effector cells.
4) Development of New Therapeutic Strategies Involving microRNAs and Other Non-Coding RNAs
Dr. Chandra received her Ph.D. from MD Anderson UTHealth Graduate School of Biomedical Sciences and completed postdoctoral fellowships at Karolinska Institute (Stockholm, Sweeden) at the Institute for Environmental Medicine - Division of Toxicology and at Mayo Clinic (Rochester, MN) in the Division of Oncology Research.
Chandra Laboratory Research:
Research in my laboratory is directed towards two broad topics:understanding how oxidative stress promotes growth, proliferation and progression in oncogene-induced hematological malignancies; and using therapeutically derived oxidative stress to induce cell death.Recent years have seen the development of a body of clinically relevant biologically targeted agents including various kinase inhibitors, farnesyl transferase inhibitors, and proteasome inhibitors. While many of these drugs are currently being tested in the clinic, their mechanism of action is often more complex than initially hypothesized. We will use some of these compounds as tools with which to better understand the biology of pediatric leukemias, and we will also address the preclinical efficacy of these agents in hematological malignancies using primary specimens from patients and animal models.
Dr. Junjie Chen earned his Ph.D. in Cell and Molecular Biology from the University of Vermont. His Postdoctoral Fellowships at Harvard Medical School focused on tumor suppressor P53, the cell cycle regulatory p21, and breast cancer susceptibility genes BRCA1, BRCA2 and control of DNA replication and repair. Dr. Chen has since held faculty positions at Mayo Foundation, Mayo Clinic College of Medicine, and the Yale University School of Medicine. He has served as Professor and Chair of the Experimental Radiation Oncology Department at MD Anderson since 2009.
Chen Laboratory Research: Our research focuses on the understanding of molecular mechanisms underlying genomic instability and tumorigenesis. Maintenance of genomic integrity following DNA damage requires the coordination of DNA repair with various cell-cycle checkpoints. The hope is that by elucidating these complex DNA damage-responsive pathways, we will reveal how deregulation of them contributes to tumor initiation and/or progression and how to take advantage of this deregulation in cancer therapy. We have been studying DNA damage signaling and DNA repair pathways since 1999. We have identified and performed in-depth functional studies of many key cell-cycle checkpoint and DNA repair proteins in several DNA damage signaling and repair pathways. Over the past few years, we expand our studies to include whole genome CRISPR/Cas9 screening and quantitative proteomics in order to achieve a comprehensive understanding of the network involved in DNA repair and determine how these proteins and pathways intersect, interact, communicate, coordinate, and collaborate for genome maintenance. In addition, we also successfully carried out genome-wide and network studies in several tumor suppressive and oncogenic pathways, including cyclin-dependent kinases, Hippo/YAP pathway, Wnt pathway, and more recently AMPK and energy stress pathway. We are combining our ability to conduct network analysis with our expertise in performing detailed mechanistic studies to establish physical and functional networks of DNA repair and other cancer-related pathways, which will facilitate our ability to exploit these pathways for cancer therapy
Dr. Chen graduated from Tsinghua University, China, received Ph.D. from University of Illinois at Urbana-Champaign (UIUC) in Electrical and Computer Engineering (ECE), and postdoctoral training from University of California at San Diego in Biochemistry and Biophysics. From 2005 to 2011, he worked for Washington University School of Medicine in St. Louis as a research faculty on cancer genomics.
Dr. Chen has designed, developed, and co-developed a set of computational tools such as BreakDancer (Nature Methods, 2009) and VarScan (Bioinformatics 2009), which have been widely used in human genetics and cancer genomics and led to discovery of cancer genes such as IDH1 (NEJM, 2009) and DNMT3A (NEJM, 2010) in AML. He has been one of the key developers and data scientists in the Cancer Genome Atlas (TCGA) and the 1000 Genomes Project (Nature 2011). Since joining MD Anderson in 2011, he has been the Director of Bioinformatics for the Institute of Personalized Therapy (IPCT), which applies bioinformatics analysis for timely, accurate diagnosis and personalized therapy. He recently focuses on developing artificial-intelligence and systems-biological approaches to construct and integrate the multiomics of cancer cell populations towards understanding the heterogeneity and the evolution of cancer and identifying targets that are useful for diagnosis and treatment.
Ken Chen Lab (KClab) Research: KClab at MDACC focuses on developing computational approaches for characterizing and interpreting heterogeneous tumor specimens and clinical data towards identifying molecular targets and biomarkers that are useful for personalized diagnosis and medicine. Recently, trainees in the lab have developed a series of methods such as Monovar (Nature Methods, 2016), SiFit (Genome Research, 2017), Cyclum (Nature Communications, 2020), and SCMER (Nature Computational Science, 2021) for single-cell variant calling, cell type/state classification, gene signature inference and developmental trajectory/lineage construction from single-cell DNA, RNA, ATAC sequencing as well as CyTOF data.
In four years at the University of Virginia, Dr. Curran completed B.A. degrees in biology and foreign affairs and a minor in computer science while receiving accolades for the best undergraduate laboratory research project. He next received a Ph.D. in Immunology from Stanford University where he was awarded the McDevitt prize for the best graduate thesis in his year. Dr. Curran was the first recipient of the prestigious American Cancer Society Levy Fellowship to fund his post-doctoral studies in the lab of Dr. James P. Allison. While pursuing his postdoctoral studies at Memorial Sloan-Kettering Cancer Center, Dr. Curran published several influential manuscripts describing how T cell co-stimulatory pathways could be modulated in tandem to mediate immunologic rejection of melanomas in mice. Dr. Curran described how combination blockade of the T cell co-inhibitory receptors CTLA-4 and PD-1 promoted the rejection of a majority of murine melanomas. This work supported the launch of a Phase I clinical trial in which greater than 50% of metastatic melanoma patients experienced objective clinical responses - a result so unprecedented that this became the first FDA-approved immunotherapy combination. In addition, his subsequent immunologic studies of 4-1BB agonist antibodies earned him the Society for the Immunotherapy of Cancer's prestigious Presidential Award. At the MD Anderson Cancer Center, Dr. Curran is an Associate Professor of Immunology as well as co-Scientific Director of the Oncology Research for Biologics and Immunotherapy Translation (ORBIT) program that coordinates development and production of clinical immunotherapeutic antibodies. The Curran Lab seeks to discover the underlying mechanisms of immune resistance in the “coldest” tumors, pancreatic and prostate adenocarcinoma and glioblastoma, so that rational therapeutic interventions can be developed to restore T cell infiltration and sensitivity to T cell checkpoint blockade (for which TIL are the substrate).
Research in the Curran Laboratory focuses on discovering mechanisms by which these immune-resistant cancers evade the host T cell response and resist checkpoint antibody therapy. Companion translational studies investigate immunologic and metabolic interventions designed to reverse microenvironmental immune suppression and re-sensitize these cancers to host immunity.
Dr. DePinho received his M.D. at Albert Einstein College of Medicine. He completed postdoctoral fellowships at Albert Einstein College of Medicine in the departments of Cell Biology and Biochemistry & Biophysics.
DePinho Laboratory Research:
Our basic and translational research program focuses on pathways and processes governing aging and age-related disorders, particularly cancer. Our experimental approach is built upon the use of unbiased computational analyses of multi-dimensional datasets, genetically engineered mouse models, and human-mouse comparisons on the molecular, cellular and physiological levels. Through MD Anderson’s Institute for Applied Cancer Science, we strive to drive basic discoveries to therapeutic and diagnostic endpoints in a systematic action-oriented culture. Our activities have focused on (i) defining the role of telomeres in governing cancer genome alterations, epithelial carcinogenesis, aging and degenerative disorder (both acquired and inherited), (ii) utilizing genetically engineered mouse (GEM) models to study human cancers with an emphasis on comparative oncogenomics and proteomics to discover and ultimately validate new genes for enlistment into drug discovery, early detection or prognostic biomarkers; there is a focus on glioma, pancreatic cancer, colorectal cancer and prostate cancer, and (iii) elucidating pathways orchestrating aging and age-related disorders with the goal of therapeutically manipulating such pathways to attenuate the incidence of age-associated diseases such as cancer, cardiomyopathy and neurodegeneration. Our mission is to convert basic knowledge into clinical endpoints that will impact on patient outcomes in meaningful ways.
Giulio Draetta trained as a physician at the University of Naples Medical School, Italy. He then pursued a postgraduate degree in Biochemistry and performed postdoctoral research at the National Cancer Institute in Bethesda and at the Cold Spring Harbor Laboratory, New York. Subsequently, he became an investigator at the Cold Spring Harbor Laboratory and then at the European Molecular Biology Laboratory, Heidelberg, Germany. In 1992, he returned to the USA to establish Mitotix, a biotechnology company focused on drug discovery in the areas of cancer, immunosuppression and infectious diseases. Dr. Draetta then returned to academia as a founding member of the Department of Experimental Oncology of the European Institute of Oncology in Milan, Italy. While in Italy, he held a joint appointment with Pharmacia Oncology where he managing the Oncology portfolio, which resulted in several IND approvals including SU11248 (Sutent®), as well as Aurora and Cdk small molecule inhibitors. In 2004, Dr. Draetta joined Merck Research Laboratories, as Executive Director and Head of Oncology Research in Boston. In 2007, he was promoted to Vice President and World Wide Basic Franchise Head, Oncology. In 2008, Dr. Draetta was appointed Dana Farber Presidential Scholar and Deputy Director of the Belfer Institute for Applied Cancer Science at Dana Farber Cancer Institute. Dr. Draetta was also Chief Research Business Development Officer at Dana Farber Cancer Institute. Since September 2011, Dr. Draetta has served as the director of the newly established Institute for Applied Cancer Science (IACS) and is a professor in the Department of Genomic Medicine.
Draetta Laboratory Research:
The focus of our research is to identify genetic elements that are required for tumor maintenance in glioblastoma, triple-negative breast cancer, and pancreatic cancer. Patients with these aggressive, lethal cancers currently have few effective therapeutic options; therefore, an in-depth understanding of the signaling mechanisms in these cancers is needed to allow the rational development of effective targeted therapies. In collaboration with the Institute for Applied Cancer Science, our lab has developed a functional genomics screening platform wherein lineage, genetic, and microenvironmental influences are carefully controlled to identify context-specific molecular targets. This novel approach allows us to rapidly identify specific genetic elements that drive or suppress tumor latency. Upon validation of targets, our lab can leverage ready access to patient samples and cutting-edge technology to rapidly translate research discoveries into improved patient care. Our early screening efforts have resulted in several on-going projects, including projects in cancer cell metabolism and epigenetics.
My lab focuses on understanding the coordination of cell division and death to control overall cell numbers in epithelia. Epithelial tissues provide an essential protective barrier for the organs they encase and are the primary sites where most solid tumors or carcinomas form. Alterations in both cell loss and proliferation have been implicated in numerous human diseases, including cancer, yet our knowledge of how these two processes influence each other to regulate cell numbers within normal epithelia remains limited. The goal of our research is to elucidate the mechanisms that regulate epithelial cell turnover while preserving barrier function. Our work has uncovered that mechanical forces guide the inter-relationship between cell death and division during homeostatic cell turnover in epithelia, and that damage elicits a separate but equally important response. We have found that cell extrusion, a process used to eliminate cells from epithelia without disrupting barrier function, is the key to driving turnover in both scenarios. To investigate extrusion in a living epithelial tissue, we developed a cellular and molecular toolset to study the epidermis of developing zebrafish. This system provides unparalleled access to analyze epithelial cell turnover in vivo and in real time. We utilize a combinatorial approach that involves timelapse imaging and reverse genetic techniques to characterize cell turnover under physiological conditions, after damage, and when extrusion is perturbed to gain a better understanding of the specific alterations that lead to epithelial pathologies and cancer.
The Futreal Laboratory aims to describe the genomic underpinnings of cancer. We seek to discover the basis for new therapy development by finding genetic mutations that explain sensitivity or resistance to therapies.
Research in the Futreal Lab focuses on assessing tumor heterogeneity by multi-region sampling and tumor evolution by collecting longitudinal samples for all types of therapeutic treatments and analyzing these samples. We collaborate with clinicians and scientists throughout MD Anderson and abroad to determine how genomic information about our patients can be used to influence clinical care by developing better diagnostic tools and aiding in treatment-decision-making processes.
Collectively, our efforts are focused on developing personalized treatments for patients with cancer.
Dr. Galko obtained his Ph.D. with Dr. Marc Tessier-Lavigne at the University of California San Francisco. His graduate studies focused on molecular and cellular mechanisms of axon guidance and his work demonstrated that guidance receptors are shed by metalloproteases as a functional guidance mechanism. Dr. Galko performed his postdoctoral studies with Dr. Mark Krasnow, at the Stanford University School of Medicine where he developed a novel genetically tractable system to study epidermal wound healing using fruit fly (Drosophila melanogaster) larvae. This system has led to the identification of conserved cellular and molecular mechanisms of wound healing. During his postdoctoral studies Dr. Galko was funded by fellowships from the American Heart Association and the Arnold and Mabel Beckman Foundation. Dr. Galko has run his research lab at the MD Anderson Cancer Center since late 2005. His lab is focused on understanding how organisms respond to tissue injury. About half of his research effort is devoted to understanding cellular and molecular mechanisms of wound-induced epithelial repair and accompanying inflammatory processes. A second more recent behavioral focus is on identifying the cellular and molecular mechanisms by which animals become locally hypersensitive to sensory stimuli following injury. The work in Dr. Galko’s lab is helping to identify conserved genes that control diverse organismal responses to injury. Dr. Galko’s lab has been funded by the American Heart Association, the March of Dimes, multiple grants from the National Institutes of Health (NINDS and NIGMS), and he was one of the initial MD Anderson R. Lee Clark Fellows in Basic Research. His research is currently supported by a five-year ‘people not projects’ R35 grant from NIGMS.
The objective of my research is to use nucleoside analogues in combination for therapy of cancer on the basis of biochemical rationale. The rationale is
achieved by understanding the biological, biochemical, and molecular mechanisms of action of each drug and the consequences on the metabolic events in intact cells and in cell free system.
A tutorial in my laboratory would provide experience in biological, biochemical, and molecular approaches to understand the metabolism and mechanism of action of the antimetabolites.
Dr. Gibbons graduated from Harvard University in 1993 (BA degree in Biochemistry), and following completion of a MS degree at The University of Texas Health Science Center – San Antonio in 1996 and a MS degree at Albert Einstein College of Medicine in 1999, he obtained his MD and PhD degrees from Albert Einstein College of Medicine in 2004. Dr. Gibbons performed his Clinical Residency at Baylor College of Medicine before joining MD Anderson Cancer Center in 2006 as a Clinical Fellow and later as a Research Fellow and Instructor. In 2010, he was appointed Assistant Professor in the Department of Thoracic/Head and Neck Medical Oncology with a secondary appointment in the Department of Molecular and Cellular Oncology. Dr. Gibbons is a physician-scientist, specializing in lung cancer medical oncology and with a lab investigating the unique characteristics of tumor microenvironment in lung cancer and mechanisms that drive cancer cells to leave the primary tumor and spread to areas outside the lung. He was selected for the Physician Scientist Award (2012-2014) and the R. Lee Clark Fellowship (2014-2016), he was awarded the Young Physician-Scientist Award by the American
Society of Clinical Investigation (ASCI, 2014) and recently elected as a member to ASCI. Dr. Gibbons is the Director of the Thoracic/Head and Neck Medical Oncology Translational Genetic Models Laboratory and Co-Leader of the Lung Cancer Moon Shot Program.
Don L. Gibbons, M.D., Ph.D. maintains a large and active lung cancer research laboratory. His lab team works in understanding the regulations of cancer cell invasion and metastasis by microRNAs (short molecules of genetic information that control the production of proteins in the
cells) and the role of the tumor microenvironment (immune cells and extracellular matrix) in those same processes. In their studies the team uses
human samples and clinical data, cell line models and mouse models.
The research in my laboratory is focused in understanding the cause of resistance of gliomas to therapies and has an important translational component. Because the current tenet on brain tumor stem cells as cells responsible for the recurrence of gliomas after surgery and for the resistance of these tumors to chemotherapy and radiotherapy, the development of cancer stem cell-based tumor models will be of great utility for uncovering the molecular mechanism responsible for the resistance of malignant gliomas to conventional therapies.
Dr. John D. Hazle is a medical physicist with over 30 years of academic experience. He is board-certified and licensed in Texas for both therapeutic and diagnostic medical physics. His primary research interests are image-guided therapy, pre-clinical imaging, novel early detection technologies and computational modeling. Dr. Hazle shares leadership of the Image Guided Therapy Lab with Dr. Jason Stafford where their work primarily focuses on developing novel approaches to image temperature using MRI. Dr. Hazle has been the Director of the NCI funded Small Animal Cancer Imaging Research Facility for 20 years and was the Director of the NCI funded Experimental Cancer Imaging Research Program from 2008-2012. He has won numerous awards, most recently MD Anderson's President's Recognition for Faculty Excellence Award in 2014.
Dr. Hazle serves on multiple institutional committees, engages as a medical imaging expert with industry partners, and is currently a journal reviewer for six peer reviewed scientific journals. He is a past President of the American Association of Physicists in Medicine and the Commission for Accreditation of
Medical Physics Education Programs. Dr. Hazle is considered a renowned expert in biomedical imaging and MRI physics. He is frequently an invited presenter at national and international conferences. Dr. Hazle also holds the Bernard W. Biedenharn Chair in Cancer Research and has a faculty appointment with The University of Texas Graduate School of Biomedical Sciences.
In the Magnetic Relaxometry Research lab we are implementing a novel technology known as nanomagnetic relaxometry for cancer-related applications - primarily early detection and assessing tumor burden in response to therapy. This technology leverages the different magnetic relaxation properties of
biologically targeted iron oxide nanoparticles from those experiencing unrestricted relaxation in the vascular or extracellular spaces. Our initial application using a second–generation MagSense™ device is for detecting human ovarian cancer cells in vivo.
After optimizing the in vitro sensitivity, we plan to test the ability of the MagSense™ instrument for detecting ovarian cancer xenografts. We also have the goal of developing sophisticated inverse problem reconstruction techniques that allow for recovery of a high dimensional relaxation field. Finally, we hope to deploy the first human prototype system in our clinics in the next few years.
Dr. Hunt earned her M.D. at the University of Tennessee Center for the Health Sciences (Memphis, TN) and completed her residency at UCLA School of Medicine, where she also served as Chief Resident in General Surgery. Dr. Hunt also completed a fellowship in surgical oncology at The University of Texas MD Anderson Cancer Center.
Hunt Laboratory Research: Our laboratory has developed a research program for identifying novel therapeutic strategies and prognostic markers based on alterations in G1/S and G2/M checkpoints in tumor cells focusing on solid tumors such as breast, sarcoma, pancreatic and lung cancers. We are currently involved in five primary areas of research, which fall into translational and basic research categories: 1) Inhibition of LMW forms of cyclin E as a therapeutic target in combination therapy for triple negative breast cancer. 2) Delineation of how the alteration of cyclin E, a G1 cyclin, could lead to the tumorigenic phenotype and determination of the oncogenic potential of the altered forms of cyclin E in breast cancer. 3) Determination of the mechanism of action of intracellular elastase and its inhibitor elafin in tumorigenesis and subsequent metastasis. 4) Examination of mechanisms of action and resistance to CDK4/6 inhibitors in ER positive breast cancer patients. 5) Identification of novel treatment strategies, targeting the cell cycle, for soft-tissue sarcomas.
The research in my laboratory is directed at defining the biological and molecular effects of the modulation of signal transduction pathways in lung, head and neck, and HPV+ cancers. We have defined novel mechanisms of sensitivity and resistance to kinase inhibitors. The three main projects are:
We recently discovered that head and neck squamous cell carcinoma (HNSCC) tumors harboring NOTCH1 mutations were more sensitive to drugs targeting the PI3K/mTOR pathway than HNSCC cell lines with wild-type NOTCH1 receptors. Goals of this project are to: Determine the efficacy of PI3K/mTOR pathway inhibition in HNSCC patients with tumors that harbor inactivating NOTCH1 mutations; Elucidate the molecular mechanism underlying PI3K/mTOR dependency and sensitivity to drugs targeting this pathway in NOTCH1 mutant HNSCC; and Identify therapeutic targets
that work in combination with PI3K/mTOR inhibitors to prevent resistance and maximize killing of NOTCH1 mutant HNSCC.
We published the first large-scale, integrated analysis to determine mechanisms of polo-like kinase 1 (PLK1) inhibitor-induced apoptosis in NSCLC by assessing gene/protein expression, gene mutation, and PLK1 inhibitor sensitivity. Mesenchymal NSCLC cell lines were more sensitive to PLK1 inhibitors than epithelial NSCLC. Indeed, inducing an epithelial phenotype increased resistance and inducing a mesenchymal phenotype increased sensitivity. We are investigating candidate pathways that underlie sensitivity to PLK inhibition.
A recently completed screen of 1122 compounds in HPV+ cancer cell lines identified clinically-relevant Aurora kinase inhibitors as effective drugs.
Integrated analysis of genomics, proteomics, gene expression, and drug sensitivity has identified several candidate pathways of resistance that are currently being studied.
Philip Jones, Ph.D.
Vice President, Therapeutics Discovery
Head of Drug Discovery, Institute for Applied Cancer Science (IACS)
Dr. Philip Jones earned his Ph.D. in organic chemistry from the University of Nottingham in the United Kingdom. Under the mentorship of Dr. Gerry Pattenden, his dissertation work focused on oxidative and reductive radical cascades towards the synthesis of polycyles. Dr. Jones completed a postdoctoral fellowship under the mentorship of Dr. Paul Knochel in organic chemistry at The Philipp University of Marburg in Germany. There, he developed novel organozinc reagents. Following a prolific international career at Merck in drug discovery and development, where he contributed to the discovery and development of agents including the PARP inhibitor niraparib. He joined MD Anderson Cancer Center in 2011 as the Head of Drug Discovery at the Institute for Applied Cancer Science (IACS), and has subsequently been promoted to as the Vice President for Therapeutics Discovery.
Dr. Jones is a drug hunter that leads a multi-disciplinary team of scientists whose mission is to identify the next generation of cancer medicines, move those into clinical trials and hopefully into clinical practice. Developing medicines is a challenging process, and engineering all the necessary properties for a single molecule to be effective in patients requires collaboration and team work across many disciplines. Jones is fortunate to work with a high-performance team, who has already delivered a drug into on-going trials at MD Anderson since its inception, with two others expected to initiate clinical evaluation during the first half of 2019. His team also has a number of promising programs coming along behind, all involving extensive collaborations with clinicians and researchers across MD Anderson.
IACS applies scientific knowledge of mechanisms driving tumor development and maintenance into the development of impactful small molecule cancer therapies. The development and validation of many therapies are underway at IACS, covering a broad array of protein target classes. Please visit the IACS website for more information.
Raghu Kalluri was born in St. Louis, Missouri and received his B.S. in Chemistry and Genetics. He received his Ph.D. in Biochemistry and Molecular Biology from the University of Kansas Medical Center and his M.D. degree from Brown University Medical School. Dr. Kalluri was a postdoctoral fellow and a research associate at the University of Pennsylvania Medical School and performed research in areas of tissue injury/repair and regeneration. In 1997 Dr. Kalluri moved to Harvard Medical School as an Assistant Professor of Medicine and as a faculty based in the Department of Medicine at the Beth Israel Deaconess Medical Center. In 2000 he was named Associate Professor and the Director of the Center for Matrix Biology, and in 2006 this program became the Division of Matrix Biology and Dr. Kalluri was appointed the Chief of the Division and also appointed as Professor of Medicine at Harvard Medical School. He held appointments in the Department of Biological Chemistry and Molecular Pharmacology at HMS, Harvard MIT Division of Health Sciences and Technology, Harvard Stem Cell Institute, and was a research fellow of the HMS Peabody Society. In 2012 Dr. Kalluri moved to The University of Texas MD Anderson Cancer Center as Professor and Chairman of the Department of Cancer Biology and the Director of the Metastasis Research Center. Dr. Kalluri currently holds the RE Bob Smith Distinguished Chair of Cancer Research. Dr. Kalluri recently received the Jacob Henle Medal from the Georg-August University in Germany to honor his discoveries related to tissue damage and regeneration, and cancer biology. He is the recipient of several mentorship and teaching awards from the Beth Israel Deaconess Medical Center, Harvard Medical School and MD Anderson Cancer Center. He is the recipient of several research excellence awards for his work on tissue damage/regeneration and cancer progression. He is the fellow of American Society of Clinical Investigation and the American Association for the Advancement of Science. Dr. Kalluri has published over 300 peer-reviewed manuscripts. Dr. Kalluri has an h-index of 121 with 63,978 lifetime citations (since 2014, h-index: 78 and 35,000 citations). Dr. Kalluri is ranked in the top 0.01% (ranked 659) of about 6.8 million scientists (covering 22 scientific fields) in the world for citation impact (https://doi.org/10.1371/journal.pbio.3000384). Dr. Kalluri has trained 107 postdoctoral fellows, 15 graduate students, and 63 undergraduate students, and 58 of his trainees hold academic positions around the world. At MD Anderson Dr. Kalluri teaches 1st year core courses for graduate students and medical students. He serves on science and health advisory panels in the USA and European Union, and on the editorial boards of several academic journals representing biology and medicine. Dr. Kalluri is a consulting editor of the Journal of Clinical Investigation and is the Deputy Editor of Cancer Research. Dr. Kalluri’s research had led to seminal discoveries in the area of tissue injury/regeneration, exosomes biology, cancer biology, and cancer metastasis. Dr. Kalluri’s work has resulted in several issued patents. Dr. Kalluri serves as an advisor to several biotechnology and pharmaceutical companies, and has co-founded five biotechnology companies. Dr. Kalluri’s laboratory is dedicated to unraveling the fundamental principles governing cancer initiation, progression, and metastasis with specific emphasis on tumor microenvironment in the context of pancreatic ductal adenocarcinoma (PDAC), triple negative breast cancer (TNBC), and glioblastoma multiforme (GBM).
Kalluri Laboratory Research: Cancer evolves to due to injury to the functional parenchyma in our body. While genetic injury, in the form of chromosomal rearrangements and gene alterations, are associated with cancer initiation and progression, the host response associated with genetic injury plays a critical role in the pathogenesis of cancer. Our laboratory is dedicated to unraveling the fundamental principles governing cancer initiation, progression and metastasis, with specific emphasis on tumor microenvironment in the context of pancreatic ductal adenocarcinoma (PDAC), triple negative breast cancer (TNBC) and glioblastoma multiforme (GBM).
The efforts of the Kalluri laboratory since 1997 led to many discoveries related to mechanism of tissue injury and regeneration, vascular biology and tumor angiogenesis, and tumor microenvironment and exosomes biology (https://www.ncbi.nlm.nih.gov/pubmed/?term=kalluri+r), and some of these findings were translated into the clinic to benefit our patients. The laboratory discoveries unraveled new understanding of the biology of cancer, offered opportunities to work with pharmaceutical industry to develop new drugs, and contributed to the formation of new biotechnology companies in partnership with the institution in an effort to fight cancer. Since moving to MD Anderson Cancer Center in 2012, the research from the Kalluri laboratory has been cited 31,876 times with an h-index of 83.
The research in our laboratory continuously evolves to reflect the knowledge gained with each study completed and the emerging new scientific information. Such plasticity allows researchers in our laboratory to ask out-of-the box questions and constantly seek novel discoveries to develop new strategies in our fight against cancer. The students and post-doctoral fellows who join our laboratory bring fresh ideas and innovative concepts to initiate projects that drive their passion for discoveries. The current research focus of the laboratory is in the following areas: tumor microenvironment in cancer biology and metastasis; tissue injury, repair and regeneration; biology and function of exosomes in cancer.
Dr. Keyomarsi completed her Ph.D. in Biochemistry at UCLA (Los Angeles, CA) and her postdoctoral training at Harvard Medical School and Dana Farber Cancer Institute (Boston, MA).
Keyomarsi Laboratory Research:
The research in my laboratory is focused on the development of novel strategies for treatment and prognosis of breast cancer by combining experimental therapeutics with cell biology while targeting the cell cycle. To this end, the laboratory is currently involved in the following areas of research which fall into translational and basic research categories.
1) Cyclin E in breast cancer: Our laboratory was the first to discover that cyclin E, a key regulator in the G1/S transition is altered in breast cancer through the generation of low molecular weight (LMW) isoforms, a result of post-translational cleavage by the elastase class of serine proteases. Specifically, we have developed in vivo models to examine the role of LMW-E in oncogenesis and discovered that the LMW-E isoforms are potent oncogenes that act early in the etiology of breast cancer [Cancer Research 2007 (PMID 17671189), 2 in 2010 (PMC2946214, PMC2888821), 2011(PMC3085722)]. We are also using these unique genetically engineered mouse models to interrogate the secondary oncogenic events induced by cyclin E early on in the neoplastic process [PLOS Genetics 2012 (PMC3315462), Cancer Research 2013 (PMC3773499)].Through the molecular analysis of the inducible murine transgenic model of LMW-E mediated tumorigenesis, we have mapped some of the early events in the pre-neoplastic mammary gland that gives rise to aggressive tumors with high metastatic potential. These events include induction of DNA damage, upregulation of several genes involved in unregulated DNA replication and G2/M transition, and specific mutations in genes, such as ALK, that is readily targetable. We then went on to elucidate the mechanism of LMW-E mediated tumorigenicity through identification and characterization of novel binding proteins and substrates for LMW-E. Protein microarray analysis identified the histone acetyltransferase (HAT) Hbo1 as a novel cyclin E/CDK2 substrate that mediates the cancer-stem-cell like phenotype. Other studies revealed that: Cyclin E is a downstream oncogenic target of PKCiota, and that activation of PKCiota by PI3K would further activate the signaling between PKCiota and cyclin [Oncogene 2016(PMC4856585)]; LMW-E is a mediator of HER-2 action in breast cancer and renders letrozole therapy ineffective in breast cancer cells that express both aromatase and ER [Oncogene 2010, (PMC2900397)]. Lastly, we identified ATP-citrate lyase (ACLY) as a novel interacting protein of LMW-E in the cytoplasm [Cancer Research 2016 (PMC4873469)]. LMW-E upregulates ACLY enzymatic activity and ACLY is required for LMW-E mediated transformation, migration and invasion in vitro, as well as tumor growth in vivo. These studies suggest a novel interplay between LMW-E and ACLY and provide an unexpected link between metabolic pathways and the cell cycle in breast cancer. Our research in this area resulted in a clinical trial -NCT01624441. More recently, we are investigating how the expression of LMW-E early in the pre-invasive breast cancer (i.e. ductal carcinoma in situ) results in induction of genomic alteration leading to an invasive carcinoma. To this end we are currently examining the role of cytoplasmic cyclin E in differentiating indolent versus high-risk ductal carcinoma in situ (DCIS) in patients, and in cyclin E inducible cell lines and mouse models. The successful completion of these studies will delineate those early oncogenic events in patients diagnosed with DCIS and provide the rationale to use LMW-E as a biomarker to identify the DCIS cases who could benefit from aggressive treatment, versus those (w/no cytoplasmic cyclin E) who can be monitored without the need for aggressive intervention.
Our laboratory then went on to show that these LMW forms of cyclin E are prognostically relevant in breast cancer patients and their activity can be targeted. Early on, we established that overexpression of the LMW-E to be a strong predictor of poor survival in breast cancer using western blot analysis [NEJM 2002 (PMID: 12432043)]. Next, we set out to decipher if the cellular localization of the LMW-E was different than full length cyclin E. Our group discovered that through elastase mediated cleavage of full length cyclin E at two distinct sites in the amino terminus of the protein, the nuclear localization signal is lost in the LMW forms. Since cyclin E can only be degraded through its anchoring by FBW7 to the proteasome in the nucleus, we showed that not only do the LMW-E reside in the cytoplasm, but that they are much more stable than full length cyclin E, which is only found in the nucleus and subject to degradation [Cancer Research 2009 (PMC2669888)]. Based on this finding, we then hypothesized that through immunohistochemistry, we can differentiate if a tumor is expressing full length cyclin E (nuclear) or LMW-E (cytoplasmic). As a result of this finding, we thendeveloped a novel immunohistochemical (IHC) assay and scoring system for both LMW-E and p-CDK2 which successfullypredicted breast cancer recurrence-free and overall survival, suggesting that these two markers of G1/S transition be used as biomarkers for aggressive breast and bladder cancer [Am. Journal of Pathology 2016 (PMC4929404)]. Most recently, weexpanded these analyses and evaluated the subcellular localization of cyclin E in breast cancer specimens from 2,494 patients from 4 different cohorts and show that in multivariable analysis, cytoplasmic cyclin E staining was associated with the greatest risk of recurrence compared with other prognostic factors across all subtypes in all cohorts [Clinical Cancer Research 2017 (PMC5441976)]. We also show cytoplasmic cyclin E staining outperformed Ki67 and all other variables as prognostic factors [Clinical Cancer Research 2017 (PMC5768442)]. Collectively, these studies suggest that cytoplasmic cyclin E is likely to identify patients with the highest likelihood of recurrence consistently across different patient cohorts and subtypes [Invited Review in Cancer Research 2018 (PMC6168358)]. These patients may benefit from alternative therapies targeting the oncogenic isoforms of cyclin E. One such therapy is based on our findings on the mechanism of action of LMW-E through alteration in DNA damage response and repair pathways identified Wee1 kinase as suitable target for LMW-E expressing tumors [Clinical Cancer Research 2018 (PMC6317865)]. A clinical trial (NCT03253679 in collaboration with Dr. Siqing Fu and Funda Meric-Bernstam) which uses AZD1775-a Wee1 kinase inhibitor as a function of cyclin E status, has been recently approved and sponsored by both Astrazeneca and CTEP and is currently accruing patients [Expert Opin Investig Drugs (PMID: 30102076)].
2) Neutrophil Elastase and breast cancer metastasis:Our observation that LMW-E could be generated from full length-cyclin E by the serine protease neutrophil elastase (NE) was an unexpected finding. Our laboratory followed up on this finding and made the novel observation that elafin, a direct inhibitor of elastase, is regulated differentially in normal versus tumor cells thorough its transcriptional downregulation by C/EBPbeta [Cancer Research 2007 (PMID: 18056453)]. These studies revealed that elafin overexpression in tumor, but not normal cells, results in the preferential induction of apoptosis in the tumor cells and elafin can eradicate xenograft tumor growth in vivo. Moreover, we reported that downregulation of elafin sensitizes human mammary epithelial cells to exogenous NE-induced proliferation, suggesting that elafin is a counterbalance against the mitogenic effects of NE, including the intracellular generation of LMW-E [Cancer Research 2010 (PMC2940941), Oncogene 2015 (PMC4362782)]. These studies have set the foundation for our recent work where we found that in patients with breast cancer, high levels of NE is prognostic for poor overall, metastasis-free, and disease-specific survival (Breast Cancer Research 2014 (PMC4326485)]. We have also shown that genetic ablation of ELANE (gene encoding for NE) or inhibition of NE by a small molecule inhibitor has the benefit of diminishing metastasis in in vivo pre-clinical models of breast cancer. In collaboration with Dr. Stephanie Watowich (Immunology) we have established a direct molecular link between tumor associated neutrophils (TANs), tumor progression and metastasis mediated by NE and, significantly, highlight a targetable pathway via NE inhibition (NE inhibitor AZD9668) for therapeutic intervention in metastatic breast cancer. This project, which will address major gaps in our understanding of how TANs enhance breast cancer growth and metastasis.
3) Mechanisms of action and resistance to CDK4/6 inhibitors: Deregulation of the CDK4/6-Cyclin D pathway in tumorigenesis has led to the development and FDA approval (palbociclib) of CDK4/6 inhibitors for the treatment of advanced estrogen receptor positive breast cancer. However, two major clinical challenges remain: i) adverse events leading to discontinuation of therapy and ii) lack of a reliable biomarker to predict response. Our laboratory has recently discovered that breast cancer cells activate autophagy in response to palbociclib, and that the combination of autophagy and CDK4/6 inhibitors induces irreversible growth inhibition and senescence in vitro, and diminishes growth of cell line and patient-derived xenograft tumorsin vivo. Furthermore, intact G1/S transition (Rb positive and LMW-E negative) is necessary and predictive of preclinical sensitivity to this drug combination and predictive of clinical response to palbociclib. Combined inhibition of CDK4/6 and autophagy was also synergistic in other solid tumor types with an intact G1/S checkpoint, providing a novel and promising biomarker-driven combination therapeutic strategy to treat breast and other solid tumors. These studies [Nature Communications 2017 (PMC5490269)] resulted in the activation of a clinical trial (NCT03774472 in collaboration with Dr. Debu Tripathy-Breast Medical Oncology) examining the synergistic activity of an autophagy inhibitor when used in combination with palbociclib and endocrine therapy.
More recently, our team have examined mechanisms of resistance to palbociclib and we reported (Clinical Cancer Research 2019 (PMID: 30867218)] that ER-positive breast cancer cells acquire resistance to palbociclib by downregulation of ER protein and DNA repair machinery and upregulation of the IL6/STA3 pathway, which is overcome by treatment with STAT3 and PARP inhibitors. Matched biopsies from patients with breast cancer who progressed on palbociclib showed downregulation in DNA repair, ER, and IL6/STAT3 as compared with their pretreatment biopsy samples. By identifying and validating these mediators (or drivers) of palbociclib resistance, a novel treatment strategy with clinically available inhibitors to STAT3 and DNA repair is currently being designed by our laboratory and colleagues (Drs. Debu Tripathy and David Tweardy-Internal Medicine) to circumvent resistance and improve clinical outcomes.
Dr. Konopleva is a Physician-Scientist, Professor, and active member of the clinical faculty in the Departments of Leukemia and Stem Cell Transplantation. Her laboratory is studying novel agents in acute myeloid and lymphocytic leukemias, focusing on BCL-2 targeting and agents targeting leukemic microenvironment and metabolism. Dr. Konopleva has extended her research to include clinical translational investigations and has developed clinical trials based on laboratory discoveries. These include BCL-2 inhibitor venetoclax, inhibitor of oxidative phosphorylation, CXCR4 inhibitors, AKT and mTOR inhibitors and hypoxia-activated prodrugs. She has also been an active mentor to trainees including undergraduate, medical and graduate students, post-doctoral fellows who have trained under her direction in support of her various laboratory grants and projects.
Dr. Krahe is a Professor in the Department of Genetics. His laboratory focuses on the identification and characterization of human rare disease genes, their mutations and underlying pathomechanisms that underlie several Mendelian diseases, using classical genetics and molecular genetics, functional genomics and mechanism-based biology approaches, including mouse and fly models. Diseases include hereditary cancer syndromes (Li-Fraumeni Syndrome and its variants, LFS /LFL ) and neuromuscular disorders (myotonic dystrophies, DM). Another focus has been the molecular characterization of sporadic cancers that are part of the LFS tumor spectrum (sarcomas, brain, leukemia, lung, head and neck) by genome-wide approaches to identify genomic, epigenomic and transcriptomic changes underlying tumor initiation, progression and metastasis. A common underlying theme of his research is the application of state-of-the-art omics methodologies towards both discovery and translational goals. In addition, Dr. Krahe is active in efforts that promote graduate and postdoctoral training and mentoring. View a complete list of Dr. Krahe's publications.
Krahe Laboratory Research Focus
Research in our laboratory focuses on the identification and characterization of human rare disease genes, their mutations and variants that underlie several Mendelian diseases.
Our goals are:
1. To understand how this genetic variation contributes to clinical phenotypes and causes human disease.
2. To identify potential entry points for therapeutic intervention by dissecting the underlying patho-mechanisms.
Dr. Jonathan M. Kurie earned his M.D. from East Carolina University and completed his Internship and Residency at the Medical College of Georgia. He was named to a two-year Biotechnology Fellowship at the National Cancer Institute at NIH and then joined Memorial Sloan Kettering Cancer Center as a Medical Oncology Fellow to complete his clinical training. Dr. Kurie is a board certified Medical Oncologist and Internal Medicine physician at MD Anderson Cancer Center. He directs a highly impactful translational cancer research laboratory and serves as Professor in the Department of Thoracic/Head and Neck Medical Oncology. Dr. Kurie is the recipient of many honors and awards for his outstanding research and is a recipient of the Gloria Upton Tennison Distinguished Professorship in Lung Cancer. Dr. Kurie has been mentoring postdoctoral fellows, graduate students, and technicians, and has received the Mentor of the Year Award at MD Anderson in 2012. He has been actively involved in the career development of several researchers, some of whom have gone on to establish them self as independent investigators and physician scientists.
Kurie Laboratory Research
The mission of the Kurie laboratory is to understand the genetic and biochemical bases for lung cancer metastasis, with an emphasis on elucidating those processes in the tumor microenvironment that regulate the metastatic propensity of tumor cells, and to develop novel therapeutic approaches on the basis of that improved understanding.
Current research in the Kurie Laboratory is centered on the investigation of mechanisms of lung cancer metastasis for the purpose of identifying novel therapeutic targets. Of foremost interest is to understand how the cellular and extracellular matrix constituents of the tumor microenvironment are controlled by tumor cells, and how signals from the microenvironment influence tumor cell behavior. In this effort, the Kurie lab uses cellular models, genetic mouse models of lung cancer that recapitulate key somatic genetic mutations and epigenetic events in tumor cells, and a tissue bank of molecularly and clinically annotated human lung cancers and matched normal lung. Research areas of interest in the laboratory include:
1. Elucidating how somatic mutations in cancer cells activate secretory vesicle biogenesis in the Golgi to drive malignant secretion and metastasis. Heightened secretion of pro-tumorigenic effector proteins is a feature of malignant cells. Yet the molecular underpinnings and therapeutic implications of this feature remain unclear. The Kurie lab identified a chromosome 1q region that is frequently amplified in diverse cancer types and encodes multiple regulators of secretory vesicle biogenesis and trafficking, including the Golgi-dedicated enzyme phosphatidylinositol (PI)-4-kinase IIIβ (PI4KIIIβ). Molecular, biochemical, and cell-biological studies showed that PI4KIIIβ-derived PI-4-phosphate (PI4P) synthesis enhances secretion and accelerates lung adenocarcinoma progression by activating GOLPH3-dependent vesicular release from the Golgi. PI4KIIIβ-dependent secreted factors maintain 1q-amplified cancer cell survival and influence pro-metastatic processes in the tumor microenvironment. Disruption of this functional circuitry in 1q-amplified cancer cells with selective PI4KIIIβ antagonists induces apoptosis and suppresses tumor growth and metastasis. These results support a model in which chromosome 1q amplifications create a unique dependency on PI4KIIIβ-dependent secretion for survival. This project offers the fellow an opportunity to gain expertise in autochthonous lung tumor development, microscopy, cell biology, and biochemistry in a novel field with strong translational potential.
2. Exploring how epithelial-to-mesenchymal transition (EMT) governs tumor cell polarity and metastasis. Metastasis is the primary cause of death in patients with lung cancer, and its genetic and biological bases are poorly understood. Progress in this area has been hampered by the lack of in vivo models that faithfully recapitulate genetic and biochemical features of human lung cancer metastasis. To address this knowledge gap, the Kurie lab has developed a series of genetically-engineered mouse models of human lung adenocarcinoma initiated by K-rasG12D expression in which secondary oncogenic mutations, including Tp53R172H expression or inactivation of Pten or Map2k4, lead to more advanced disease but differ in the degree to which they promote disease advancement. Their transcriptional profiling studies revealed that poor-prognosis human lung adenocarcinomas were highly enriched in genes differentially expressed between primary and metastatic tumors in mice that develop widely metastatic lung adenocarcinomas owing to expression of K-rasG12D and p53R172H (KP mice). They showed that KP mice harbor disease whose progression closely mirrors that of poor-prognosis lung adenocarcinoma in patients and that lung adenocarcinoma cell lines derived from these mice provide a useful platform for the discovery of clinically relevant, pharmacologically actionable metastasis drivers. Metastatic tumor cells derived from KP mice switch reversibly between epithelial and mesenchymal states in response to extracellular cues; this plasticity is critical for metastasis and is driven by mutual antagonism between transcription factors that activate EMT (e.g., ZEB, SNAIL, and TWIST family members) and microRNAs that target the EMT-activating transcription factors (e.g., miR-200 and miR34 family members). They are currently studying how the EMT regulatory axis governs tumor cell polarity and the formation of actin-based cytoplasmic protrusions (e.g., filopodia and lamellipodia) by controlling vesicular trafficking through endocytic recycling, retrograde, and anterograde pathways. This project offers fellows an opportunity to gain expertise in advanced microscopy (point-scanning high-resolution confocal microscopy, spinning disc microscopy, total internal reflection fluorescence), tumor cell biology, and mouse modeling.
3. Elucidating how extracellular signals govern tumor cell metastatic activity. To address this question, the Kurie lab has created murine and cellular models of human lung cancer in which tumor cells and collagenous stroma can be visualized microscopically in 3 dimensions and in real time. They showed that tumor cells gain metastatic properties by inducing the formation of a particularly stable type of collagen cross-link driven by high expression of lysyl hydroxylase 2 (LH2), a collagen lysyl hydroxylase. They also showed that this enzyme is secreted and modifies both intracellular nascent collagen strands and extracellular triple helical collagen molecules, and that LH2-driven cross-links enhance the migratory and invasive properties of tumor cells. They generated the first crystal structure of a collagen lysyl hydroxylase and used that knowledge to identify small molecule inhibitors of LH2 from high throughput screens. This project offers fellows an opportunity to gain expertise in enzymology, collagen biochemistry, and tumor cell biology in a novel field with strong translational potential.
4. Identifying and targeting pro-metastatic cancer-associated fibroblasts (CAFs). CAFs are mesenchymal cells of diverse origins. CAFsexhibit a high degree of intra-tumoral heterogeneity that allows them to execute multiple pro-metastatic functions in the tumor microenvironment. The Kurie lab comprehensively analyzed CAF heterogeneity and its molecular underpinnings in lung adenocarcinoma. Among ~ 80,000 fibroblasts analyzed, heterogeneity was greater in lung adenocarcinoma than it was in idiopathic pulmonary fibrosis, a disease associated with high lung cancer risk from progressive fibrosis. At the single-cell transcriptomic level, CAFs segregated into distinct clusters, 2 of which demonstrated hallmarks of strongly activated fibroblasts and were correlated with shorter survival. In co-culture with lung adenocarcinoma cells, CAFs acquired transcriptomic hallmarks of poor-prognostic clusters, a shift driven by an EMT-dependent secretory program in tumor cells. The capacity of CAFs to enhance metastasis in mice and to generate invasive structures in 3-dimensional collagen gels depended on tumor cell EMT state. Adherence to collagen was a targetable vulnerability in poor-prognostic CAF clusters.
Research Interests are:
Tumor immunology; cytotoxic T lymphocytes; dendritic cells; antigen presentation; immunosuppression in cancer.
Using the tumor immunopeptidome to guide the design of personalized cancer vaccines. Although T-cell checkpoint blockade has shown great promise for inducing long-term tumor regressions in cancer patients, the majority still succumb to their disease following an initial response to treatment. A very serious current limitation to most immunotherapeutic interventions is a lack of specificity in immune system activation: IL-2 and the checkpoint blockade
approaches activate T lymphocytes non-specifically, often inducing serious autoimmune side effects.
One of the major barriers in immunotherapy today is a lack of knowledge about the vast majority of antigenic targets that are presented by MHC class I (MHC-I) molecules on individual patient tumors. Having knowledge of these MHC-I ligands will provide unprecedented opportunities to target these tumor targets clinically, resulting in increased effectiveness and less treatment side effects. To this end, our group has spent the past year focused on identifying MHC-I ligands directly from the surface of patient tumor cell lines and biopsies using a combined approach encompassing MS-based proteomics, genomics, and bioinformatics. In collaboration with Dr. David Hawke of the Proteomics Facility, we have now optimized the peptide elution and mass spectrophotometry techniques, allowing us to successfully identify thousands of potentially antigenic peptides from melanomas, sarcomas, colon, breast, and pancreatic patient tumors. It is hoped that this project will lead to the development of personalized cancer vaccines not restricted by tumor type, patient HLA haplotype, or limited by a lack of known target tumor antigens.
Improving antitumor immunity through modulation of MHC class I antigen presentation. MHC class I–mediated antigen presentation is the central focus of the immune response during naïve cytotoxic T lymphocyte (CTL) priming and cytotoxic effector recognition of target cells. We have studied both of these systems to elucidate the biological role of the MHC-I cytoplasmic domain, which contains two relatively uncharacterized, highly conserved phosphorylation sites and a putative ubiquitination site. My laboratory is particularly interested in how these post-translational modifications can influence CD8+ T-cell mediated antitumor immune responses. Through site-directed mutagenesis, we have shown that there are two opposing motifs within the MHC-I cytoplasmic domain, and that alteration of these motifs can dramatically alter antitumor CTL priming efficiency by dendritic cells (DCs). These findings could have important implications for human cancer vaccines, particularly if we identify druggable targets to enable modulation of MHC-I antigen presentation in DCs to improve CTL priming. In addition, our group has started to delineate a connection between the MAPK signaling pathway and MHC-I trafficking and antigen presentation in melanoma cells. In particular, we have shown that drug inhibition of oncogenic BRAF(V600E) leads to a rapid redistribution of MHC-I molecules to the plasma membrane, a property that appears to be dependent on one of the two conserved cytoplasmic phosphorylation sites. We are currently using the peptide elution / mass spec analysis to assess how such drug treatments may affect the immunopeptidome of tumor cells. It is hoped that these findings will have an impact clinically, by helping to guide the design of rational treatment regimens that combine targeted agents with immune-based therapies.
Exploring the link between oncogene activation and immune suppression in cancer. Although T cell-based immunotherapies have the potential to induce long-lasting complete remissions in cancer patients, their efficacy is often limited by immunosuppressive cells and factors found within the tumor microenvironment that protect the tumor from immune recognition and killing by CTLs. While several tumor-specific mechanisms of immunosuppression have been described, how immunosuppression is initiated and sustained within neoplastic lesions to promote tumor growth remains to be fully elucidated. Our lab has recently shown that immunosuppression can be initiated by oncogenic BRAF(V600E), which is mutated to a constitutively active form in about half of melanoma patients. This pathway of immunosuppression involves a molecular cross-talk between BRAF(V600E)-expressing tumor cells and tumor-associated fibroblasts (TAFs) and features the upregulation of a transcriptional program involving multiple immunomodulatory genes known to inhibit immune responses. Key features of this cross-talk involve oncogene-induced expression of IL-1 a and IL-1 b by melanoma tumor cells, which in turn triggers the upregulation of T-cell inhibitory molecules PD-L1, PD-L2, and COX-2 by TAFs. Collectively, our results suggest that cancer-associated chronic immunosuppression may be relieved through the pharmacological inhibition of the MAPK signaling pathway in tumor cells and predict that such interventions would synergize strongly with immunotherapy.
Dr. Ma Received her Ph.D. from Memorial Sloan Kettering Institute and Cornell University - Weill Graduate School of Medical Sciences (New York, NY) and completed a postdoctoral fellowship in Cancer Biology at the Whitehead Institute for Biomedical Research (Cambridge, MA).
Ma Laboratory Research:
The overarching goal of the Ma laboratory is to understand the molecular mechanisms of tumor progression and metastasis. Since its founding in 2010, the Ma Lab has played a major role in establishing models of microRNA-mediated regulation of metastasis, epithelial-mesenchymal transition, and therapy resistance (Nature Medicine 2012, PLoS Genetics 2014, Nature Communications 2014, Cancer Research 2016, etc), and in rectifying models of long non-coding RNA (lncRNA) regulation of metastasis (Nature Genetics 2018 – a paradigm-shifting study that establishes the framework for rigorous characterization of lncRNAs). In addition to RNA-related research, the Ma Lab also discovered the deubiquitinases for key cancer proteins; some of these deubiquitinases are promising anti-tumor and anti-metastatic targets (Nature Cell Biology 2013, Nature Cell Biology 2014, Cell Reports 2018, Nature Communications 2018, etc). Our work has been confirmed and cited by many groups (Dr. Ma’s Google Scholar citations: 10,000 as of 2018). Multiple former postdocs from this lab have landed independent faculty positions.
Current interests include: (1) establishing new paradigms for RNA functions and mechanisms in tumor progression and metastasis; (2) screening for deubiquitinating enzymes that promote tumorigenesis, metastasis, or therapy resistance; and (3) investigating novel regulators and regulations of tumor radioresistance, drug resistance, and anti-tumor immunity.
Dr. Maitra received his M.B.B.S. from All Indian Institute of Medical Sciences (New Delhi, India) and completed fellowships at Univeristy of Texas Southwestern Medical Center (Dallas, TX) in Anatomic Pathology, Molecular Pathology, and Pediatric Pathology. He completed his residency at UT Southwestern in Anatomic Pathology and a fellowship in Gastrointestinal Pathology at Johns Hopkins University School of Medicine (Baltimore, MD).
Maitra Laboratory Research:
Pancreatic ductal adenocarcinoma (PDAC) is the fourth most common cause of cancer-related mortality in the United States, accounting for over >37,000 deaths each year in this country, and is forecast to become the second most common cause of cancer-related deaths by 2030. This alarming increase is already evident in the state of Texas, where the incidence of PDAC has risen by an astounding 32% over the last decade (http://www.dshs.state.tx.us/tcr). Nationwide, the overwhelming majority of patients with PDAC (~85%) are diagnosed with distant metastases or with locally advanced disease, rendering them surgically inoperable. Notably, even within the minority of pancreatic cancer patients that undergo surgical resection, as many as 70% will die of recurrence within the next two years. This sobering statistic implies that PDAC is likely to invade and become “micrometastatic” at a relatively early stage of disease, which has been underscored by recent findings in experimental models. As detailed in my curriculum vitae, the central themes of my research over the last decade have focused on the genetics and therapy of PDAC. Thus, the multi-disciplinary translational research team, of which I am an integral member of at Johns Hopkins University, has elucidated the genomic landscape of not only PDAC, the most lethal primary malignancy arising from the pancreas, but also each of the individual variant tumors within this organ, such as pancreatic neuroendocrine tumors (PanNETs) and cystic neoplasms of the pancreas (Jones et al Science 2008; Jiao et al, Science 2011; Wu et al, Sci Transl Med 2011; Wu et al, PNAS 2011). These unprecedented insights into the genome of pancreatic neoplasia over the last few years have now provided my own laboratory with unique opportunities to model the cognate entities in genetically engineered mice, with a long term goal of developing both early detection and targeted therapeutic approaches. This prolific “team science” (recognized this year by the American Association for Cancer Research with the 2013 Team Science Award) is emblematic of the translational research approach I hope to bring to the Sheikh Ahmed Center for Pancreatic Cancer Research Center, of which I am the Scientific Director.
Selected research questions that my laboratory is pursing in translational PDAC research:
Project 1: Functional annotation of the PDAC genome
The recent publication of the International Cancer Genome Consortium (ICGC) data on over 100 PDACs has established the definitive genetic landscape of PDACs (Biankin et al, Nature, 2012; Dr. Maitra is a member of this consortium). The ICGC has identified numerous alterations that putatively cooperate with the near ubiquitous KRAS mutations in PDAC pathogenesis, including highly significant recurrent mutations of TP53, SMAD4, CDKN2A/p16, MLL3, ARID1A, TGFBR2, SF3B1, UTX, etc.. While the tumor suppressor role of several of the encoded proteins is well established (TP53, SMAD4, CDKN2A/p16), others remain virtually unknown vis-à-vis their function, and the effector pathways through which they participate in pancreatic carcinogenesis. In many instances, even the overarching mechanism – tumor suppression versus oncogenic potentiation – remains unknown. The importance of tissue specific contexts in gene function mandates that we explicitly interrogate the role of mutational alterations using cognate PDAC models. These studies have already led to some unexpected insights in our laboratory. For example, the mixed leukemia lymphoma (MLL) gene family encodes for histone methyltransferases, and typically undergoes gain-of-function (GOF) alterations in leukemia. On the contrary, reported somatic mutations of MLL3 (observed in ~10% of PDAC) are loss-of-function (LOF), as evidenced by our data in human PDAC lines, as well as in a novel conditional mouse model of pancreas-specific Mll3 loss (unpublished data). Further, we have identified a hitherto undescribed role for MLL3 protein in DNA repair, which suggests that tumors bearing somatic mutations of MLL3 might be susceptible to DNA damaging agents. We are systematically querying recurrent alterations that cooperate with mutant KRAS in PDAC initiation and/or progression, using a broad compendium of in vitro and in vivo functional studies (such as in spontaneously metastatic orthotopic models and low-passage patient-derived human PDAC cell lines). Effector pathways are being interrogated using a combination of global profiling approaches, including ChIP-Seq and RNA-Seq. For the most compelling mutations, we are developing genetically engineered mouse models (GEMMs). The availability of CRISPR/Cas9 systems for high efficiency introduction of targeted genomic deletions will allow us an opportunity to rapidly introduce LOF mutations in both PDAC cell lines and in autochthonous models. Finally, given the overarching translational focus of our laboratory, we are performing high throughput screens for synthetic lethal interactions using either de novo or engineered mutations in PDAC lines. Functional annotation of the most significant cooperating mutations with KRAS that contribute to pancreatic carcinogenesis will not only provide key biological insights into this lethal neoplasm, but also potential new avenues for therapeutic intervention.
Project 2: Development of a “liquid biopsy” program in PDAC
In patients that present with either de novo or recurrent metastatic PDAC, a fine needle aspiration or a core needle biopsy is performed for diagnosis, but the acquired specimen is typically adequate for only perfunctory molecular assays. More importantly, the nature of the specimen generally precludes the opportunity to establish a viable patient-specific preclinical model that can be used for elucidating molecular underpinnings of cancer recurrence and chemoresistance in advanced disease. In fact, nearly all of the patient-derived xenograft (PDX) and cell lines in existence have been established from primary tumors, even as the major source of mortality in most patients remains metastases. We are developing a “liquid biopsy” program in PDAC, which will enable the isolation of viable circulating tumor cells (CTCs) from a single vial of patient blood. Studies published in the last year show that viable CTCs can be isolated and cultured ex vivo from patients with underlying solid tumors, such as lung and breast cancers, and the resulting preclinical models provide an effective surrogate for therapeutic decision making and predicting patient outcomes. Through ex vivo molecular annotation combined with expansion of these CTCs in 3-D culture as spheroids, and in mice as PDXs, we hope to improve our understanding of mechanisms underlying genetic heterogeneity, patterns of tumor recurrence and treatment failure in patients with PDAC.
Project 3: Targeting tumor survival networks in the PDAC microenvironment
PDAC is unique amongst solid tumors in the floridness of its stromal response to invasion, a phenomenon labeled as desmoplasia. The PDAC tumor microenvironment (TME), however, is comprised not only of cancer-associated fibroblasts (CAFs), but also a multitude of additional cell types, such as T- and B-cell subsets; and cells of granulocyte/monocyte lineage, including macrophages, mast cells, and myeloid-derived suppressor cells (MDSCs), amongst others. Many of these cellular components have pertinent roles in the survival and dissemination of neoplastic cells. At MD Anderson, my laboratory has initiated multiple projects directed at perturbing survival networks within the PDAC TME. Salient examples include (a) dissecting the molecular and metabolic circuitries underlying paracrine interactions between neoplastic cells and the host TME; (b) generating a robust antitumor immune response by blocking co-inhibitory molecules expressed on the PDAC cell surface or immunosuppressive cytokines in the peritumoral milieu; (c) identification of immunogenic mutant epitopes on PDAC cells that can be targets of vaccine-induced adaptive immune response; and (d) high-throughput screens for identification of small molecules that can selectively deplete barriers to therapeutic efficacy in the PDAC TME, specifically drugs targeting CAFs and immunosuppressive MDSCs. These, and other experiments, will be facilitated by our access to autochthonous models harboring the compendium of immune cells observed in human PDAC.
Dr. Sendurai A. Mani received his Ph.D. in Molecular Biology from the Indian Institute of Science in Bangalore, India. He completed his Postdoctoral Fellowship at Whitehead Institute and Massachusetts Institute of Technology, where he focused efforts on cancer biology. He joined the faculty at MD Anderson as Assistant Professor in 2007. Dr. Mani currently serves as Associate Professor in the Department of Translational Molecular Pathology at MD Anderson.
Mani Laboratory Research:
The Mani lab welcomes talented and motivated individuals with a Ph.D. or M.D./Ph.D. for TRIUMPH Postdoctoral Fellowship positions. Candidates with experience in cancer biology, cell biology, molecular biology, and/or mouse developmental biology are preferred. Despite the advent of advanced diagnosis and treatment options, metastases account for more than 90% of deaths among cancer patients. We and others have demonstrated that carcinoma cells, which are initially confined to the primary tumor site by the continued expression of cell-cell adhesion molecules, acquires mesenchymal morphology, increased migration, invasion, and metastatic properties by activating a latent embryonic program known as epithelial-mesenchymal transition (EMT). Additionally, cancer cells leaving their primary sites during metastasis recreate tumor histopathologically similar their tissue of origin at the metastatic site. Therefore, we hypothesized and demonstrated that the cancer cells also acquire stem cell properties via EMT in addition to migratory and invasive capabilities. Both cancer stem cells (CSCs) and the EMT program are independently shown to be responsible for promoting metastasis and the acquisition of resistance to standard of care therapies and we found that these two are indeed, intertwined. We therefore put forward the notion that the EMT-signaling pathways may offer a diagnostic and therapeutic window for detecting and treating metastasis. At present, our laboratory is investigating the biology of metastasis at the molecular level and developing ways to diagnose and treat metastases. To this end, we employ epigenetics, metabolism, miRNA, long non-coding RNAs, and bioinformatics approaches. In addition, we utilize various in vitro and in vivo tumor model systems, including tissue-specific, inducible, transgenic mouse models. Our laboratory currently focuses in four areas:
1) Identification and functional characterization of genetic regulators of invasion, metastasis, EMT, and CSCs
2) Identification and characterization of immune regulators of metastasis
3) Identification, characterization, and development of small molecule inhibitors for preventing and treating therapy resistance and metastasis
Dr. Mazur received his BSc and MSc in Molecular Biology from Warsaw University in Poland. He earned his PhD in Molecular Biology and Cancer Research from Max Planck Institute of Biochemistry in Germany. Dr. Mazur joined the Departments of Genetics and Pediatrics at Stanford University for his Postdoctoral Fellowship, where he studied molecular mechanisms of MAPK signaling regulation in pancreatic cancer. He was promoted to Instructor in the Department of Pediatrics at Stanford University and later joined MD Anderson Cancer Center in the Department of Experimental Radiation Oncology as Assistant Professor.
Mazur Laboratory Research:
We are seeking strong candidates for high-impact, cross-disciplinary research projects within the pancreatic and lung cancer research program in our lab. Current projects are supported by several multi-year grants (NIH, CPRIT, AACR, AGA, LCRG) and in collaboration with industry (Sanofi) and private sponsors (Andrew Sabin Foundation) focused on the development of novel targeted and immuno-therapeutics, including:
Project 1. Adoptive immunotherapy (CAR-T cell-based therapy)
We work on basic and translational tumor immunology with focus on T cell biology and adoptive immunotherapy of cancer with the goal of developing new treatments for patients. The candidate will utilize advanced molecular biology techniques to improve the activity of immune cells and to investigate underlying mechanisms using realistic animal models and human samples. The Postdoctoral Fellow will work on creation of potent chimeric antigen receptors (CARs), and manipulation of co-stimulatory and signaling molecules. The Postdoctoral Fellow will be directly involved in translation of this work into the novel pre-clinical platform of adoptive immunotherapy for solid cancers. Our translational research platform takes advantage of immunocompetent pre-clinical mouse models integrated with Magnetic Resonance Imaging (MRI) for real time tumor monitoring and co-culture organoid tumor models using IncuCyte® live cell analysis system established in the lab (Nature Medicine, 2013, Nature Medicine, 2015, Cell, in press, 2018)
Project 2. Biochemistry (novel and “orphan” enzymes substrates discovery)
We aim to determine the functions and mechanisms of action of novel lysine methyltransferases in pancreas and lung tumorigenesis. Using CRISPR/Cas9 genetics screening we identified novel and “orphan” enzymes important in driving cancer progression and drug resistance. The Postdoctoral Fellow will utilize unique mouse strains that we have generated, cutting-edge proteomics, gene-editing and biochemical technologies, and the collaborative effort of our research groups (project performed in collaboration with Dr. Or Gozani’s Lab at Stanford University world class expert in proteomics and enzyme biology) to identify enzymatic activities and their function in cancer therapy (Nature, 2014 and Genes and Development 2016, Cell, in press, 2018). If warranted, the prospective Fellow will work with our collaborators at the Institute for Applied Cancer Science (IACS) to generate inhibitors targeting the identified enzymes for therapeutic intervention and test the compound using our established pre-clinical platform (Nature Medicine, 2015).
Project 3. Genetics and pharmacogenomics (multiplex CRISPR/Cas9 animal models of cancer)
We integrate CRISPR/Cas9-mediated genome engineering with conventional genetically-engineered alleles in mouse models of human lung and pancreatic cancers to create a high-throughput experimental pipeline to interrogate wide spectrums of tumor genotypes. Quantitative assessment of genotype-specific tumor responses to a panel of targeted therapies will generate a pharmacogenomic map that will guide patient treatment. The project is based on our recently published method for in vivo CRIPSR-mediated somatic-engineering in mice developed in collaboration with Dr. Tyler Jacks’ Lab at MIT (Nature Medicine, 2015). This method enables new comprehensive ways to combine mouse models and next-generation sequencing approaches to identify the dynamic interplay between specific tumor genotypes and the response to therapy. The project takes advantage of the “mouse clinic” approach utilizing pre-clinical mouse models integrated with MRI T2 real time tumor monitoring, as well as PDX and organoid tumor models established in Mazur lab (Nature Medicine, 2015).
Dr. McCrea is a Professor in the Department of Genetics. Current work asks how the shape of neurons is determined, which is key to understanding nervous system development and how it can go wrong in disease. In the context of the neuron as well as other cell types/ tissues, the lab focuses upon the biology of catenin proteins. For this purpose, it employs primary cells, cultured cells, and animal systems. Catenins additionally have notable roles in cancer, with prominent examples being beta-catenin, p120-catenin, and delta-catenin. The McCrea laboratory has revealed new catenin complexes and functions, including actions at the cytoskeleton and cell junctions (e.g. via small-GTPases), and functions in the nucleus/ gene control (e.g. Wnt-pathway). The lab’s purpose is to probe how catenins promote normal development, to assist in understanding dementia, aging, mental illness, and cancer. Coexisting with these scientific enterprises, Dr. McCrea is active in promoting graduate and postdoctoral training and mentorship. View a complete list of Dr. McCrea's publications.
The McCrea lab uses primary neurons, developing frog embryos and cell lines, we seek to understand the biology of essential catenin proteins. Catenins transduce developmental (e.g. canonical-Wnt pathway) and pathologic signals into the nucleus. Being multi-functional, they further bind and modulate cadherins in regulating cell-cell adhesion at junctions and influence small-GTPases that determine the behavior of cytoskeletal structures, cell shape and cell movements. Many key interactions and functions of the catenins are yet to be discovered.
Catenin Biology / Neural Development / Vertebrate Development / Intracellular & Nuclear Signaling
We are asking how the catenins within cells help to advance vertebrate development, for example:
1) How are the shapes of neuronal dendrites modulated by delta-catenin and its protein partners?
2) Beyond beta-catenin, do multiple catenins act in parallel to promote canonical-Wnt signaling?
3) What are the distinct versus shared functions of catenins in the nucleus?
Jeffrey N. Myers, M.D., Ph.D., F.A.C.S.
Professor, Department of Head and Neck Surgery
Alando J. Ballantyne Distinguished Chair of Head and Neck Surgery
Director or Translational Research, Division of Surgery
Director of Research, Department of Head and Neck Surgery
Deputy Chair for Academic Programs, Department of Head and Neck Surgery
Dr. Myers earned his Ph.D. in Biochemistry and his M.D. at the University of Pennsylvania School of Medicine (Philadelphia, PA). He completed his residency in Otolaryngology-Head and Neck Surgery at the University of Pittsburgh School of Medicine (Pittsburg, PA) and a fellowship in Head and Neck Surgery at University of Texas MD Anderson Cancer Center (Houston, TX). Dr. Myers leads a basic and translational research program and his primary research interests are in the role of p53 mutation in oral cancer progression, metastasis, and response to treatment.
Myers Laboratory Research:
Squamous cell carcinoma, tongue neoplasms, p53 gain of function mutations
Dr. Navin earned his Ph.D. in Molecular Genetics and completed his postdoctoral fellowship in Cancer Genetics from Cold Spring Harbor Laboratory and Stony Brook Univeristy (Cold Spring Harbor, NY).
Navin Laboratory Research:
My laboratory focuses on understanding the role of clonal diversity and evolution in the context of tumor progression in breast cancer. Intratumor heterogeneity has been difficult to delineate in tumors using standard genomic methods that are limited to making bulk measurements that mask the genetic differences between cells and subpopulations. To address this problem, we pioneered the development of the first single cell DNA sequencing method (Navin et al. 2011, Nature). This study demonstrated the technical feasibility of sequencing the genome of a single mammalian cell. This study played a central role in establishing the new field of single cell genomics, which has shown tremendous growth over the past 5 years due to myriad of applications in diverse fields of research and biomedicine. My group continues to lead the cancer field of single cell genomics. We have applied single cell sequencing technologies to study mutational evolution and aneuploidy in breast cancer patients. Our studies revealed a punctuated model of copy number evolution in triple-negative breast cancer, in which complex aneuploid rearrangements are acquired in short evolutionary bursts at the earliest stages of tumor progression, followed by stable clonal expansions (Gao et al. 2016, Nature Gen.; Navin et al. 2011, Nature). These data have challenged the long-standing paradigm of gradual copy number evolution during tumorigenesis. Our group has also discovered a mutator phenotype in breast cancer cells that lead to the generation of many rare subclonal mutations that are likely to play an important role in therapy resistance (Wang et al. 2014, Nature).
Our group has remained at the forefront of the field, and continues to developed novel single cell DNA sequencing technologies to measure genome-wide copy number profiles (Baslan et al. 2012, Nature Prot), single cell whole genomes (Wang et al. 2014, Nature), single cell exomes (Leung et al. 2015, Genome Biol.) and multiplexed targeted panels in single cells (Wang and Leung et al. 2016, Nature Prot.). We also have a major focus on developing computational methods to analyze large-scale single cell DNA sequencing datasets, including statistical methods for estimating copy number profiles (Baslan et al. 2012, Nature Prot; Wang et al. 2014, Nature), probabilistic methods to infer phylogenies (Gao et al. 2016 Nature Gen.; Davis et al. 2016, Genome Biol) and Bayesian likelihood genotype models for detecting DNA variants (Zafar et al. 2016, Nature Methods). Current work is focused on using single cell DNA and RNA sequencing methods to study tumor initiation, invasion, metastasis, and therapy resistance in breast cancer. We also work closely with oncologists at MD Anderson to translate our single cell sequencing technologies into the clinic, for applications in early detection, non-invasive monitoring and improving diagnostic modalities. These efforts are expected to have a major impact on reducing morbidity and improving the quality of life for breast cancer patients.
Dr. Roza Nurieva is an Associate Professor in the Department of Immunology at MD Anderson Cancer Center. Research in her lab aims to elucidate the molecular basis of T cell mediated immune responses, and how abnormal immune regulation leads to immunodeficiency, autoimmunity and cancer. In recent work, Dr. Nurieva’s lab showed that transplantation of Grail-deficient T cells into a mouse model of lymphoma was sufficient to inhibit the growth of established tumors, suggesting Grail is a potential target to improve the cancer immune response. Continuing studies will help us to understand the function of the immune system, and will, therefore, help develop approaches to design drugs against cancer, as well as against autoimmune disorders.
Our goal is to study how developmental signaling and stem cells are engaged in tissue homeostasis, regeneration and cancer, and use that knowledge to develop biomarkers and therapy for human diseases. We utilize genetically engineered mice and organoids with a specific interest in Wnt signaling.
Wnt signaling plays key roles in governing various cellular processes during embryogenesis, organogenesis, and tissue homeostasis. We are exploring how Wnt signaling controls tissue stem and progenitor cells and orchestrates tissue regeneration. Aberrant activation of Wnt signaling contributes to cancer. Given the crucial roles of Wnt signaling in tissue homeostasis and regeneration, direct targeting of Wnt signaling as a cancer treatment is challenging. To overcome this, we are in the study of new molecules, cancer-specific regulators of Wnt signaling, in pre-clinical model systems.
We are interested in understanding how developmental signaling and stem cells are engaged in tissue homeostasis, regeneration, and cancer.
Dr. Piwnica-Worms received his Ph.D. in Cell Physiology and his M.D. at Duke University (Durham, NC) and completed his residency at Harvard Medical School and Brigham and Women's Hospital (Boston, MA) in Diagnostic Radiology, where he also served as Chief Resident. Dr. Piwnica-Worms completed his fellowship in Magnetic Resonance Imaging also at Harvard Medical School and Brigham and Women's Hospital and did his Postdoctoral Research Fellowship in Physiology at Duke University.
Dr. Piwnica-Worms (David) Laboratory Research:
Genomic lesions within incipient cancer cells in collaboration with alterations in the microenvironment contribute to neoplastic progression. Tumor cells can modulate the surrounding microenvironment to promote the progression of cancer through intrinsic oncogenic pathways. However, the importance of the host microenvironment in neoplastic progression, independent of tumor manipulation, is also underscored by studies demonstrating that many stromal and immune cell types stimulate growth of pre-neoplastic and neoplastic cells along with promoting drug resistance. Given these observations, understanding the complex interactions between genomic lesions and tumor microenvironment in animal models is crucial to understanding mechanisms of transformation and uncovering new anti-cancer therapies. Thus, non-invasive imaging technologies have become increasingly important for providing spatial and temporal resolution of biological structure and function, particularly for defining the context of gene expression and protein function, and their regulatory mechanisms within the proper physiologic context of cellular micro-environments. Molecular imaging is used to interrogate protein processing, protein-protein interactions, gene expression and flux through metabolic pathways in real-time in cells, live animals, and humans, and is an increasingly useful tool for understanding signal transduction, pharmacodynamics, and the pathobiology of human diseases in vivo, facilitating development of effective therapies.
Dr. Piwnica-Worms earned her Ph.D. in Microbiology and Immunology at Duke University (Durham, NC) and completed a Research Fellowship in Pathology at Harvard Medical School and Dana-Farber Cancer Institute (Boston, MA).
Piwnica-Worms (Helen) Laboratory Research:
The major goals of my research program are to delineate how the cell division cycle is regulated in unperturbed cycling cells (cell cycle control); how cell division is delayed by replicative- and genotoxic stress (checkpoint control); how cancer cells derail these regulatory pathways; and ultimately to use this information to treat human disease. Clinical, preclinical and basic studies in breast and prostate cancer are a major focus of the laboratory. We are actively involved in designing and analyzing the results of Phase I/II clinical trials aimed at translating our fundamental knowledge of cell cycle- and checkpoint-control into improved targeted therapies for breast cancer patients. Recognizing that a key challenge facing breast cancer researchers today is the lack of good preclinical models for studying human breast cancer, we are working with primary human breast tumors obtained directly from breast cancer patients. These tumors are being propagated in the humanized mammary fat pads of immune compromised mice for our preclinical studies (HIM models). Many of these models metastasize out of the mouse mammary gland to distant mouse organs, including bone and lung. We are identifying the molecular changes associated with the acquisition of metastasis in this model. In addition, we are developing mouse models that enable regulatory pathways to be studied non-invasively and repetitively in living mice using molecular imaging strategies, with a particular focus on p21 and CDC25A.
The Schadler lab has two broad categories of interest: tumor vascular biology and the utilization of exercise as a therapeutic adjuvant. We use mouse models of pediatric bone sarcomas and melanoma to a) determine the molecular pathways in tumor endothelium that regulate the vascular response to exercise; b) determine how the anti-tumor immune response is changed by exercise; c) determine whether exercise and diet modifications can be used to protect against chemotherapy-induced cardiac toxicity; d) identify potential therapeutic targets in tumor endothelium to induce tumor vessel normalization. We also collaborate closely with clinicians in order to perform clinical trials in which cancer patients participate in exercise studies.
Our research program focuses on understanding replication fork protection, which likely is a novel tumor and disease suppression pathway. Specifically, we have recently discovered a new pathway for DNA replication fork protection involving breast cancer and Fanconi Anemia tumor susceptibility genes distinct from DNA repair, which suppresses genomic instability by stabilizing RAD51 filaments to protect against nucleolytic degradation of stalled replication forks. With a now growing list of known tumor suppressors protecting nascent DNA strands, our research is set out to obtain key knowledge on the role of this new pathway in patient tumor cells, during transcription and in metabolism to eventually devise effective treatment strategies.
DNA replication is a master key to cancer growth and therapy. We focus on molecular mechanisms of DNA replication fork stability that suppress familial inherited cancers and provide a unique window on what has gone awry and the underlying disease principles. We discovered and defined replication fork protection, a major genome stability pathway. We developed and apply new methods for single cell and single molecule analyses at replication forks. Our hypotheses and efforts foremost are informed by human biology and by active collaborations with clinicians (hereditary heme, breast cancer, ovarian cancer), and our work is complemented by collaborations with bioinformaticians and structural biologists. Overall, our research aims to provide foundational knowledge to inform advanced therapeutic strategies and develop functional biomarkers to predict disease cause and response.
Our research centers on three major areas:
1) Genome instability gene functions in mitochondria, which we found suppress inflammation. We examine how breast cancer susceptibility genes (BRCA) and Fanconi Anemia suppressors function at mitochondrial DNA replication forks to control the immune response and metabolism, and how patient mutations can derail such control.
2) The molecular cause for Fanconi Anemia and hereditary heme malignancies for insights on cancer biology. We test patient samples and have established an exciting Fanconi Anemia mouse model recapitulating key features of the human disease to understand cause and effect.
3) BRCA/p53 collaborations at the DNA replication fork. We identified unexpected roles for BRCA and p53 in replication stability. We are investigating how genome stability proteins function at the replication fork and how this determines therapy response and resistance.
I integrate biophysics and biochemistry to help address challenges relevant to medicine and biotechnology. I strive to characterize macromolecular complexes including their conformations and interactions that control biological outcomes to mechanistically inform on cancer biology and treatment strategies. My group does this by developing and employing multi-disciplinary biophysical methods with biological collaborations to join structures to biology. Importantly, my projects inform and cross-pollinate one another, so we are more able to successfully and efficiently understand how macromolecular complexes and pathway intersections impact outcomes in cells and humans. Besides hypothesis-driven research, my laboratory develops advanced technology to bridge the gaps from molecular structure to quantitative, predictive cell biology: we do this by creating, testing, and providing technology for insights on dynamic macromolecular conformations and interactions that impact biological outcomes including structure-based design and microbially-inspired solutions to challenges in human health.
I develop funded programs that focus structural biology on medical relevant challenges, such as my Structural Biology of DNA Repair (SBDR) NCI program project. My RO1 lab projects center on cellular stress responses (DNA repair impacting genome integrity and tumorigenesis, reactive oxygen regulators, pathogenesis factors, metalloenzymes, RNA, plus enzyme and inhibitor design). My research and training include advanced methods development for technologies defining complexes and conformations in solution and at high resolution. I designed, built, and run the synchrotron beamline SIBYLS at the Advanced Light Source (ALS) to integrate small angle x-ray scattering (SAXS) with high-resolution crystal structures for predictive biology - see http://www.bl1231.als.lbl.gov/. SIBYLS had ~1200 users in the last 5 years and >15 HHMI groups.
Our work on structural biology and SAXS includes introducing new equations for analyzing X-ray scattering data for flexible macromolecules and complexes. We introduced a novel SAXS invariant, the first discovered since the Porod invariant 60 years ago. Furthermore, we develop new metrics for accurate structures, conformations, and assemblies in solution. Our analyses are providing parameters to better assess flexibility, measure intermolecular distances and data to model agreement, reduce false positives, and define resolution.
The SIBYLS facility I built and run (funded by my IDAT and MINOS programs) supports efficient progress in developing and testing the technologies and in characterizing protein interactions, complexes, and conformations in solution and at high resolution. These resources support our growing interests in applying both solution and single crystal methods to structure-based inhibitor design relevant to developing chemical knockouts to complement genetic knockouts, and as eventual therapeutics. The synergy between basic research and technique advancement is allowing us to contribute to basic knowledge and advances relevant to human diseases.
Overall, my group’s research and technology development aim to bridge the gaps from molecular structure to quantitative, mechanistic, and predictive cell biology for organisms. I view this as the age of cell biology with sequencing advances and systems biology opening doors to game changing contributions to fighting human diseases and applying biotechnology. A missing element needed to make current scientific contributions more powerful is a mechanistic understanding at the molecular level that leverages the sequence information and provides a bottom up quantitative and predictive knowledge to objectively link with top down systems biology. I therefore aim to develop tools and technologies to address biology grand challenges, and to connect dynamic structures to biological outcomes. I apply synthetic biology and inhibitor design to learn more about how biological systems work, and to develop useful agents for medicine and nanotechnology. By leveraging my project efforts by strategic collaborations, my goal is to help apply these advances to therapeutics for pathogenesis, degenerative diseases and cancer, and for biotechnology useful for sustainable health in humans.
Dr. Taniguchi received his M.D. and Ph.D. in Cell and Developmental Biology from Harvard University. He completed both a clinical residency in radiation oncology and a research fellowship in radiation oncology Stanford University before joining MD Anderson as faculty in the Division of Radiation Oncology. Dr. Taniguchi is a former Barry M. Goldwater Scholar, a Rhodes Scholar, a Cancer Prevention Research Institute of Texas Scholar, and a McNair Scholar. He is a former Sabin Family Fellow, the recipient of an American Society of Clinical Investigators Young Investigator Award and a Sidney Kimmel Scholar. His research is featured in high impact journals such as Nature Medicine, Science Translational Medicine, and Cell. Dr. Taniguchi serves as an Assistant Professor in the Department of Radiation Oncology. In addition to his research, he is a board-certified radiation oncologist specializing in the treatment of gastrointestinal cancers and subspecializing in cancers of the pancreas, rectum, and anus.
Taniguchi Laboratory Research:
The Taniguchi lab studies the biology of hypoxia as a platform to oncogenesis and normal tissue regeneration in the context of gastrointestinal cancers. His basic and translational laboratory studies incorporate tissues and patient samples from ongoing clinical trials with animal and cell models to fully interrogate complex biology. The basic and translational lab has four main areas, all of which have an associated ongoing clinical trial or one about to be activated:
1. Modulating the immunosuppressive microenvironment of pancreatic cancer by manipulating hypoxia signaling. Pancreatic cancer is among the most hypoxic of all human tumors, and we believe this physico-chemical property for the tumor microenvironment drives cancer growth, immune evasion and treatment resistance. We have identified a pathway where HIF signaling in activated stellate cells drives the immunosuppressive phenotype and are actively investigating this biology in clinical samples and mouse models.
2. The role of the microbiome in gastrointestinal cancers. The microbiome of the intestinal tract cohabitates with many GI cancers that we study, including pancreatic, colorectal and anal cancers. We have multiple projects that examine the metagenomics landscapes of these tumors and normal tissues and study the mechanisms of these changes in animal models, including germ-free genetically engineered mice.
3. Exploiting hypoxia for tissue regeneration. We have found that a class of drugs called EGLN inhibitors are hypoxia mimics that trigger hypoxia biology without causing frank low oxygen tension. We use these drugs to stimulate stem cell growth in intestinal stem cells as well as in models of hippocampal and skin regeneration.
4. Exploring the role of hypoxia on mitochondrial function. We have found that pancreatic cancer mitochondria have defects in mitochondrial dynamics, whereby they are often fragmented but somehow highly functional. Some of this function may be dependent on hypoxia dependent gene expression. We explore how to exploit the metabolic vulnerability for therapeutic gain.
We have found that pancreatic cancer mitochondria have defects in mitochondrial dynamics, whereby they are often fragmented but somehow highly functional. Some of this function may be dependent on hypoxia dependent gene expression. We explore how to exploit the metabolic vulnerability for therapeutic gain.
The focus of the Tweardy Laboratory is understanding and modulating the host damage response to microbial and traumatic injury to treat disease. The clinical research interests of David Tweardy, M.D., include the role of apoptosis and inflammation in susceptibility to infection, especially following injuries.
His basic research interests over the past 20 years have centered on cytokines and cytokine signaling and currently focus on the second messenger—signal transducer and activator of transcription (STAT) 3—critical in the signal transduction pathway of over 40 cytokines, as well as the role of STAT3 in inflammation and cell surivival.
Dr. Wargo’s career commitment is to advance the understanding and treatment of disease through science. After completing her medical degree, she entered surgical residency training at the Massachusetts General Hospital/Harvard Medical School where she became interested in the biology and treatment of cancer. During her training, she completed 2 fellowships in surgical oncology with a focus on immunotherapy for cancer.Dr. Wargo was recruited to the Division of Surgical Oncology at Massachusetts General Hospital in July 2008 and had an active research laboratory focusing on melanoma tumorigenesis and immunotherapy for cancer. One exciting finding involved data describing the effect of BRAF-targeted therapy on tumor antigen expression in melanoma as a basis for combining targeted therapy and immunotherapy in the treatment of this disease. Dr. Wargo validated those findings in patients treated with BRAF inhibitors. She has continued critical studies to better understand the effects of BRAF inhibition on immune responses in melanoma, and established a unique set of serial tumor biopsies and blood samples from patients enrolled on clinical trials on BRAF inhibitors. Through analysis of these samples, she contributed significantly to the world literature regarding resistance mechanisms and the effect of targeted therapy on anti-tumor immunity.
Wargo Laboratory Research:
Jennifer A. Wargo, M.D. runs a translational research laboratory studying the genetics of melanoma and other cancers with the goal of understanding what allows them to grow, spread and evade the immune system. The research of the Wargo Lab is focused on using genetic targeted therapy to arrest the growth of these cancers and to make them more visible to the immune system. The lab is currently developing clinical trials incorporating what she has learned in the laboratory to treat patients with cancer Her efforts in this regard have been nationally recognized, and she has several research grants for this work, including starting PRIME TR (Program for Innovative Microbiome and Translational Research). In addition to her important work in the laboratory, Wargo has focused on minimally-invasive surgical techniques for the treatment of skin diseases, including skin cancer. As part of the Surgical Oncology department at MD Anderson Cancer Center, she has contributed to improving management for patients with skin cancer and other skin disease.
Watowich Laboratory Research:
The Watowich lab at MD Anderson investigates fundamental mechanisms that regulate innate immune responses in cancer, and how cells in the innate immune system contribute to or suppress cancer growth, how innate cells affect response to cancer treatment, and roles for innate cells in immune-related adverse events (irAE) during cancer immunotherapy. We aim to utilize information from our studies to develop novel, highly effective anti-tumor therapies with low toxicity. We are specifically interested in understanding how dendritic cells, the professional antigen-presenting cells of the immune system, contribute to cancer eradication, immunotherapy responses, and irAEs. Our primary tumor models include melanoma, osteosarcoma, and breast cancer. We combine our expertise in innate immune regulation with clinical and translational collaborators across MD Anderson, allowing us to bridge fundamental studies with pre-clinical models and translational advances in cancer treatment.
Dihua Yu, M.D., Ph.D.
Professor, Department of Molecular and Cellular Oncology
Hubert L. & Olive Stringer Distinguished Chair in Basic Sciences
Deputy Chair, Department of Molecular and Cellular Oncology
Dr. Yu earned her M.S. in Neuro-Cardio Physiology and her M.D. at Capital University of Medicine (Beijing, China). She went on to earn her Ph.D. in Molecular Biology and Cancer Biology from MD Anderson UTHealth Graduate School of Biomedical Sciences.
Yu Laboratory Research:
My laboratory functions as a bridge connecting basic & translational cancer research to important issues in cancer patient care. In the new era of personalized cancer therapy, several new challenges are emerging. Our research is focused on tackling these new challenges. First, we are dissecting mechanisms of resistance to targeted- and immuno- therapies, and designing counteracting strategies to make patients respond better to anti-cancer therapies. Second, we are decoding cancer metastasis, especially brain metastasis, and designing effective therapies based on mechanistic understanding. Third, we are developing early detection, prevention, and intervention strategies for breast cancer and colon cancers. For example, we are using 2D and three-dimensional (3D) cell culture models and various preclinical animal models, including cancer cell xenograft, patient-derived xenograft (PDX), transgenic, and knockout mouse models, as well as tissue and plasma specimens from patients. Our recent research areas also include, but are not limited to, stem cells and breast cancer initiating cells, molecular imaging of cancer progression, dysregulation of i) metabolism, ii) tumor microenvironment; iii) epigenetic modifiers, and iv) immune responses, and their roles in cancer progression, metastasis, and resistance to therapies.
To understand how oncogenic signaling pathways and tumor microenvironment regulate cancer development and metastasis. To search for biomarkers and context-specific therapeutic targets for personalized cancer medicine.
Dr. Zhao’s laboratory in the Experimental Radiation Oncology (ERO) department is interested in the functional genomics of prostate cancers with two primary directives: (1) understanding how oncogenic signaling pathways and tumor microenvironment regulate cancer development and metastasis, and (2) searching for biomarkers and context-specific therapeutic targets for personalized cancer medicine.