Faculty Spotlight - Summer 2020
The CPRIT TRIUMPH Program congratulates Dr. Cassian Yee and collaborators from Rice University on the grant funding of their work to design a point-of-care device for the rapid identification of patients with severe cases of COVID-19 and who are likely to require the greatest degree of medical assistance. Development of the proposed inexpensive microfluidic device will allow for automation of the immune cell quantification process. Dr. Yee is a TRIUMPH faculty mentor and Professor in the Department of Melanoma Medical Oncology at MD Anderson Cancer Center.
CPRIT TRIUMPH Faculty
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.
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.
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. 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, M.D., Ph.D.
Sr. Vice President, Discovery and Platforms
Chief Academic Officer, ad interim
Professor, Department of Genomic Medicine
Sewell Family Chair, Department of Genomic Medicine
Co-Leader, Moon Shots Program
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.
Dr. Heymach earned his M.D. and his Ph.D. in Neuroscience from Stanford University. He completed a Clinical Internship and Residency in Internal Medicine at Brigham and Women’s Hospital in Boston, MA followed by a Clinical Fellowship in Medical Oncology at Dana-Farber/Partners Cancer Care Medical Oncology Fellowship Program. He is a board certified Medical Oncologist and Internal Medicine physician. Dr. Heymach is a Professor in the Cancer Biology department and serves as Chair of the Thoracic/Head and Neck Medical Oncology Department at MD Anderson. He holds the David Bruton, Jr. Chair in Cancer Research, he is a Co-Leader of the MD Anderson Lung Cancer Moon Shot Program, and directs a prolific translational cancer research laboratory at MD Anderson Cancer Center.
Dr. Heymach’s Research Laboratory:
The mission of Dr. Heymach’s laboratory is to improve the clinical outcome of lung and head and neck cancer patients through scientific advances in understanding the molecular drivers of the disease, the development of predictive biomarkers of drug sensitivity, and the identification of new therapies and mechanisms of resistance. Dr. Heymach’s research has both basic and translational components and employs integrative approaches of genomic and proteomic analyses of human samples coupled with an extensive collection of cell lines and mouse models to advance the understanding of lung cancer and head and neck malignancies. Dr. Heymach’s laboratory interests include investigating new approaches for targetable pathways in EGFR, KRAS, and STK11/LKB1 mutant NSCLC, small cell lung cancer (SCLC), and other solid tumors, and mechanisms of resistance to immunotherapy in lung cancer.In addition, his laboratory has considerable broad expertize in the development of blood-based markers and in the testing of angiogenesis inhibitors in lung cancer and other solid tumors. The studies conducted in Dr. Heymach’s laboratory have a bench to bedside approach as preclinical studies can be validated through connections with vast clinical datasets, and promising findings can be rapidly translated into the clinic. His research efforts are focused on the following areas:
1. Investigating new targetable pathways and mechanisms of therapeutic resistance in EGFR mutant NSCLC including:
- Therapeutic targeting of subgroups of EGFR and HER2 mutant NSCLC (e.g. exon 20 and exon 18 EGFR mutations). Recently, Dr. Heymach’s laboratory identified a novel therapy for tumors bearing EGFR and HER exon 20 mutations that have remained refractory to all standard therapies. Through in vitro and in vivos creens, coupled with molecular modeling, they identified a highly active drug, poziotinib that had previously been tested for standard EGFR mutations and was discontinued (Robichaux et al. Nature Med 2018). Based on this preclinical data a phase II trial of poziotinib is being conducted in MD Anderson and initial results indicate high anti-tumor activity with best objective response of PR (partial response) in 55% of 44 evaluable patients. His laboratory efforts are currently focused on identifying resistance mechanisms to poziotinib as well as investigating new treatment strategies for exon 18 EGFR and HER2 mutant NSCLC, including new TKIs and immunotherapy.
- Investigating EMT and other mechanisms of tyrosine-kinase inhibition (TKI) resistance and immunosuppression in EGFR mutant NSCLC. Dr. Heymach’s laboratory has made several fundamental advances in elucidating mechanisms of resistance to EGFR TKIs and developing new strategies to overcome this resistance in EGFR-mutant lung cancer. His laboratory identified key pathways driving invasiveness and EGFR inhibitor resistance, including an EGFR/HIF/MET axis; the VEGF/KDR pathway and epithelial-to-mesenchymal transition (EMT). His laboratory also identified chronic stress hormones as drivers of EGFR inhibitor resistance through beta-2 adrenergic receptors (Nilsson et al. Science Trans Med 2017). This resistance can be blocked by beta-blockers and based on this study, a randomized trial using the beta-blocker propranolol is in development. His laboratory has also a focus on investigating the molecular determinants of immunologically inert tumors like EGFR or LKB1 mutant NSCLC, and to test innovative approaches for enhancing antitumor immunity like CART-cell therapies, NK-cell therapies, drug-conjugated antibodies and novel therapeutic combination approaches.
- Investigating new approaches for targeting drug-resistant persister cells in EGFR mutant NSCLC. Tumor cells (EGFR mutant cells) that are not killed by initial treatment with TKIs -termed persister cells- can be present in the residual tumor and may remain quiescent or clinically invisible for prolonged periods of time to eventually progress to become drug resistant cells. Dr. Heymach’s laboratory is currently involved in the study of these drug-resistant persister cell population through innovative techniques (single-cell RNA/DNA sequencing) and mouse models to find new effective targeting approaches in early stage EGFR mutant NSCLC.
2. Investigating novel immunotherapy approaches for lung cancer, including:
- Studying genomic determinants of response to immunotherapy in NSCLC. Dr. Heymach’s laboratory and collaborators identified that co-occurring genomic alterations in three tumor suppressors (P53, LKB1, and CDKN2A) are critical drivers of this heterogeneity and define subsets of KRAS-mutant NSCLC that have distinct biology, immune profiles, and therapeutic vulnerabilities (Skoulidis et al. Can Disc 2015). His laboratory, working in collaboration with a multi-institutional team of clinical investigators, investigated the genomic determinants of response to immunotherapy and recently identified mutations in LKB1 as the strongest predictor of immunotherapy resistance in lung adenocarcinoma (Skoulidis et al. Can Disc 2018). Dr. Heymach is the PI of an R01 grant investigating the mechanisms underlining these immune-inert tumors to develop precise immunotherapy approaches for enhancing antitumor immunity and overcoming resistance by using well-established preclinical NSCLC models. Examples of these approaches include the targeting of potential metabolic vulnerabilities of tumors, the restoration of antigen-presentation machinery, and the targeting of immunosuppression-related cytokines.
- Identifying new approaches to enhance immunotherapy in SCLC. New therapeutic strategies are desperately needed for SCLC. Dr. Heymach’s laboratory has elucidated the signaling “circuitry” of NSCLC and SCLC and identified PARP-1 and EZH2 as novel therapeutic targets for SCLC (Byers et al. Can Disc 2012). This has led to the development of two clinical trials of PARP inhibitors, which will be conducted in MD Anderson and other sites. One particular understudied feature of SCLC is that it has a relatively immunosuppressed phenotype with relatively low levels of infiltrating T-cells and evidence of reduced antigen presentation. Recently, atezolizumab (anti-PD-L1) has been FDA-approved for its use in combination with chemotherapy in SCLC but further studies are needed to enhance the efficacy of these agents. To address this need, Dr. Heymach’s laboratory in conjunction with a multidisciplinary team, focus on the identification of new targets and the development of novel approaches for SCLC including CART-cell therapies, agents that protect immune cells from chemotherapy-induced toxicity, the targeting of epigenetic modulators, etc.
3. Identification of blood-based biomarkers and mechanisms of resistance to angiogenesis inhibitors.
Dr. Heymach’s laboratory showed that the majority of changes associated with therapeutic resistance occur in stromal cells (including endothelial cells), rather than tumor cells and that targeting these stromal pathways including FGFR2, EGFR, and MET could delay the emergence of resistance (Cascone et al. J Clin Invest 2011; Xu et al. Oncogene 2010). These findings have impacted the clinical development of angiogenesis inhibitors and their biomarkers as they have suggested rational combination regimens and revealed that biomarker approaches in this area must take into account not only tumor cells, but also stromal and host effects. His laboratory also developed CAF signatures predicting response in early stage NSCLC, head and neck, and metastatic renal cell carcinoma patients (Nikolinakos et al. Can Res 2010; Hanrahan et al. JCO 2010; Kopetz et al. JCO 2010; de Groot et al, CCR, 2011).
4. Identification of new therapies and biomarkers for predicting drug response in head and neck cancer.
Dr. Heymach has also investigated new therapeutic targets, signaling pathways, and resistance mechanisms in head and neck cancers using high-throughput profiling. This includes the identification of an Axl/PI3K/PD-L1 axis as well as focal adhesion kinase (FAK) as drivers of radioresistance in HNSCC (Skinner et al. Clin Can Res 2016 and 2017). His laboratory has also recently identified that NOTCH1 activating mutations identify a distinct subgroup with poor prognosis and a propensity to bone and liver metastasis (Ferrarotto et al. JCO 2017). Clinical trials based on all three of these findings are currently in progress or development; the trials targeting the NOTCH1 pathway in ACC could lead to the first targeted agent approval for this disease.
5. The clinical testing of new therapies and treatment paradigms for lung cancer. Dr. Heymach’s laboratory conducted the first randomized trial of local consolidative therapy (LCT), consisting of surgery or radiotherapy, for oligometastatic NSCLC patients with non-progressive disease after initial systemic treatment. The study showed a significant prolongation in progression free survival (12 months in the LCT arm vs 3.9 months for the standard systemic approach) and a delay in new metastases (Gomez et al. Lancet Onc 2016). This LCT approach has already changed the standard for a subset of lung cancer patients, and its use may broaden based on these ongoing studies. Currently, Dr. Heymach’s group is expanding this approach to incorporate immunotherapy (the LONESTAR study) and TKIs (the NORTHSTAR study).
Dr. Heymach earned his MD and his PhD in Neuroscience from Stanford University. He completed a Clinical Internship and Residency in Internal Medicine at Brigham and Women’s Hospital in Boston, MA followed by a Clinical Fellowship in Medical Oncology at Dana-Farber/Partners CancerCare Medical Oncology Fellowship Program. He is a board certified Medical Oncologist and Internal Medicine physician. Dr. Heymach is appointed as Professor in the Cancer Biology department and serves as Professor and Chair of the Thoracic/Head and Neck Medical Oncology Department at MD Anderson. He is the David Bruton, Jr. Chair in Cancer Research, a Co-Leader of the MD Anderson Lung Cancer Moon Shot Program, and directs a prolific translational cancer research laboratory at MD Anderson Cancer Center.
Heymach Laboratory Research
The mission of the Heymach research laboratory is to improve the clinical outcome of non-small cell lung cancer patients through scientific advances in understanding the molecular drivers of lung cancer, identification of predictive biomarkers of drug sensitivity, and identification of mechanisms of therapeutic resistance and novel strategies to overcome resistance. Dr. Heymach’s research has both basic and translational components and employs integrative approaches of genomic and proteomic analyses of human lung cancer coupled with an extensive collection of cell lines and murine models of lung cancer to advance the understanding of lung malignancies.
Key lab interests include investigating frequent drivers of lung cancer such as LKB1 loss, oncogenic KRAS, and EGFR activating mutations. Preclinical studies are designed to identify novel therapeutic strategies as well as approaches to overcome therapeutic resistance. In addition, the Heymach Lab has considerable effort directed at identifying mechanisms by which lung cancer cells escape immune surveillance and designing treatment regimens to best employ immunotherapy strategies. Studies conducted in the Heymach lab have a bench to bedside approach as preclinical studies can be validated through connections with vast clinical datasets, and promising finding can be rapidly translated into the clinic. Research efforts are currently focused on the following areas:
1. Investigating mechanisms regulating angiogenesis, metastatic spread, and resistance to VEGFR and EGFR inhibitors.Although VEGF and EGFR inhibitors have already demonstrated clinical benefits in patients, resistance unfortunately develops in almost all cases. A major goal of Dr. Heymach’s laboratory is to understand the mechanisms by which this occurs, and use this information to develop combination regimens to combat anti-angiogenic agents and EGFR inhibitors. For example, while most studies of drug resistance have focused on tumor cell mutations, his lab found that resistance to VEGF inhibitors is primarily mediated by stromal pathways (Cascone et al, J Clin Investigation, 2011) including the EGFR and FGFR pathways, and that by blocking these stromal pathways, vascular remodeling and therapeutic resistance could be blocked. They also identified a critical axis of EGFR→HIF→MET as a regulator of metastatic spread in NSCLC (Xu et al, Oncogene, 2010).
2. Development of blood-based biomarkers for angiogenesis inhibitors. The tumor microenvironment is influenced not only by tumor cells but a wide range of host-derived factors including the inflammatory system and the endogenous angiogenic response. Understanding the factors influencing tumor angiogenesis therefore takes a broader approach of assessing tumor cells, stroma, and host factors. The Heymach lab has used a number of different approaches for developing markers for predicting response and resistance to angiogenesis factors and other targeted agents. This includes profiling circulating cytokines and angiogenic factors (CAFs) which we have used to develop markers for several VEGF inhibitors, as well as circulating myeloid cells and endothelial cells (Nikolinakos et al, Can Res, 2010; Hanrahan et al, JCO, 2010; Kopetz et al, JCO, 2010; de Groot et al, CCR, 2011). This approach has also identified a potential role for the HGF/MET, FGFR, and myeloid recruitment pathways in driving tumor angiogenesis and drug resistance. A new platform for capturing circulating tumor cells (CTCs) enables the group to investigate the use of CTCs as potential biomarkers.
3. Develop proteomic and gene expression markers for predicting drug response. The Heymach lab takes a systems biology approach to develop proteomic, genomic, and gene expression profiles in NSCLC cell lines and tumors and used this to identify key pathways or processes driving tumor progression and drug resistance. This includes extensive profiling of >100 cell lines and tumor specimens which are then correlated with clinical outcomes.
In collaboration with other members of the THNMO Department and the Biostatistics and Bioinformatics Departments, they are also conducting analysis of several clinical trials of targets agents that will permit them to test and potentially validate markers identified in their preclinical studies, and discover new markers and oncogenic pathways.
4. Understanding how oncogenic pathways can lead to metastatic spread and resistance to anticancer therapies.
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:
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.
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.
Eugenie Kleinerman, M.D.
Professor, Department of Pediatrics and Department of Cancer Biology
Mary V. and John A. Reilly Distinguished Chair
Eugenie S. Kleinerman, M.D., is Professor of the Division of Pediatrics. She is board certified in pediatrics, holds the Mary V. and John A. Reilly Distinguished Chair and is also a Professor of Cancer Biology. A native of Cleveland, OH, Dr. Kleinerman received her BA degree from Washington University in St. Louis, her medical degree from Duke University, then completed her pediatric residency at the Children’s National Medical Center in Washington, DC and her fellowship at the National Cancer Institute in Bethesda, MD. She was a Senior Investigator at the NCI-Frederick Cancer Research facility for 3 years before being recruited to MD Anderson in 1984. Dr. Kleinerman rose through the ranks from Assistant Professor to Professor. She served as Division Head of the Division of Pediatrics from 2001 to February 9, 2015, the first women Division Head at MD Anderson.
Dr. Kleinerman is internationally recognized for my scientific and clinical expertise in sarcomas, (osteo and Ewing’s) and for her successes in translational research. Her 33 year career has focused on understanding the biology and mechanisms involved in the metastasis of osteosarcoma (OS) to the lung and identifying novel therapeutic strategies for both cancers. She pioneered the use of a unique immunotherapeutic agent, liposome-encapsulated muramyl-tripeptide (L-MTP), for children with relapsed OS lung metastases. Dr. Kleinerman's preclinical laboratory research, funded by R01 grants from the NCI, supported the initiation of phase I and phase II clinical trials done at MD Anderson Cancer Center. These trials demonstrated that L-MTP activated the tumoricidal properties of macrophages following administration, prolonged disease-free and overall survival in relapsed OS patients and could be combined with chemotherapy. The success of these trials led to a national phase III trial sponsored by the Children’s Oncology Group which demonstrated efficacy in patients that received L-MTP with chemotherapy, decreasing the mortality rate by 30% at 8 years. This phase III trial led to the approval of L-MTP by the European Medicine Agency (EMA). L-MTP is now part of standard treatment for OS patients in the UK, and other European countries, Mexico, South America, Turkey, and Korea. This demonstrates her success in translational research and identifies Dr. Kleinerman as an expert in the field of sarcoma translational research. Her preclinical research also demonstrated the efficacy of aerosol gene and aerosol chemotherapy against OS lung metastases by upregulating the expression of Fas on the tumor cell surface. These studies led to the initiation of clinical protocols using aerosol therapy. Her research program has been funded by the National Cancer Institute for over 30 years. She has >195 articles and 21 book chapters.
Kleinerman Laboratory Research:
Dr. Kleinerman's career has focused on understanding the biology and mechanisms involved in Osteosarcoma (OS) lung metastasis and the pathways that control vascular development in Ewing’s sarcoma (ES). She has defined molecular pathways that control tumor vascular expansion, and the pathways that influence the metastatic potential of sarcoma to the lung. She developed a unique transplant model to identify how BM cells contribute to the vascular expansion in ES. She showed that vasculogenesis is critical to the expansion of Ewing’s vasculature; that EWS-FLI-1 transcriptionally down-regulated Caper-β which mediates alternative splicing of VEGF which is critical to the vasculogenesis process; that Notch signaling, DLL4, and the SDF-1a/PDGF-B pathway controlled the differentiation of BM cells into tumor vascular pericytes; that EWS-FLI-1 upregulated REST; and that REST controlled the formation of the ES vascular pericyte layer. Dr. Kleinerman developed a mouse model of human OS lung metastases and demonstrated that Fas expression inversely correlates with the metastatic potential of OS cells. She demonstrated the efficacy of aerosol gene and chemotherapy against OS lung metastases which led to clinical protocols in pediatrics. She pioneered the use of immunotherapy in children with OS lung metastases, demonstrating that MTP-PE activated the tumoricidal properties of macrophages. Dr. Kleinerman led the phase II trials & was Co-PI in the phase III trial which showed that MTP + chemotherapy decreased the death rate by 30% at 8 years. Thus she has a successful track record of translating preclinical laboratory investigations into clinical trials. This Energy Balance (diet & exercise) research focus is a new area for her. She was recently awarded a Multidisciplinary Research Grant from the Institution on Energy Balance in Pediatric Oncology which provided the preliminary data. Dr. Schadler (Co-PI) and Dr. Kleinerman recently published 1 review article and have 1 research manuscript accepted for publication. Their goal is to decrease acute and late cardiotoxicity in Pediatric cancer patients..
Dr. Koong earned his M.D. at Northwestern University and his Ph.D. in Cancer Biology from Stanford University, where he completed residency training in Radiation Oncology. He served in many capacities as research faculty and an attending physician at Stanford University for more than two decades before joining MD Anderson in 2017. Dr. Koong serves as Professor and Chair of the Department of Radiation Oncology and is the recipient of the Robert C. Hickey Endowed Chair for Clinical Care. He is a Fellow of both the American College of Radiology (ACR) and the American Society for Radiation Oncology (ASTRO).
Koong Laboratory Research:
The Koong laboratory is a translational cancer research laboratory focused on the development of therapies to target signaling pathways regulated by the tumor microenvironment and to develop biomarkers that are predictive of clinical outcomes. Current clinical research interests are focused on the development and application of highly targeted radiotherapy techniques for gastrointestinal malignancies, particularly involving the use of stereotactic body radiotherapy (SBRT)/stereotactic ablative radiotherapy (SABR) for pancreatic and liver cancers. The Koong laboratory also studies the role of endoplasmic reticulum (ER) stress in tumor growth and metastasis.
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.
Li Ma, Ph.D.
Associate Professor, Department of Experimental Radiation Oncology
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. 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. 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. 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).
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. 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.
Dr. Katy Rezvani is Sally Cooper Murray Chair in Cancer Research, Professor of Medicine, Chief of the Section for Cellular Therapy, Director of Translational Research and Medical Director of the GMP Facility at MD Anderson Cancer Center. She is the Principal Investigator on numerous grants and trials. Dr. Rezvani has over 150 peer-reviewed publications related to Immunotherapy, Cellular Therapy and Hematology/Oncology and hematopoietic transplantation. She has an active research laboratory program in transplantation immunology where the focus of her research group is to study the role of natural killer cells (NK) cells in mediating immunity against hematologic disorders such as acute leukemia and myelodysplastic syndromes as well as solid tumors, and to understand the mechanisms of tumor-induced NK cell dysfunction. The goal of these studies is to develop strategies to enhance NK cell effector function against tumors by genetically engineering the cells to enhance their in vivo antileukemic activity and persistence. She is the recipient of multiple grants and awards, and her laboratory program in transplant immunology has led to the approval and funding of a number of Phase I/II studies of immunotherapy in patients with hematologic malignancies as well as solid tumors such as glioblastoma.
Rezvani Laboratory Research:
1. Engineering NK cells as a novel cancer immunotherapy.
Current work in our laboratory centers on developing novel strategies to enhance NK cell effector function against various tumors by genetically engineering the cells to enhance their anti-cancer activity and persistence. We are pursuing this by engineering NK cells to express CAR against multiple cancer targets. Our laboratory recently demonstrated that ex vivo expanded NK cells expressing a CAR against CD19 and the IL15 gene can dramatically enhance the in vivo persistence and anti-tumor activity of CAR-NK cells in a mouse model of lymphoma. We have translated this strategy to the clinic and a first-in-human clinical trial is currently underway at our center.
2. Adoptive cell therapy using viral specific T cells.
Another area of interest in our laboratory is the use of virus-specific T cells as adoptive therapy for the treatment of viral infection. Allogeneic stem cell transplantation is a potential curative treatment for hematologic malignancies including leukemia and lymphoma but a number of factor such as the high mortality rates associated with viral infection and graft vs host disease (GVHD) after transplant limit the clinical success. Our goal is to develop engineered T cells using different gene editing tools including TALEN or CRISPR to make them resistant to current cancer immunosuppressive drug regimens and use it as an off-the-shelf T cell therapy for immediate clinical use. Data from our clinical trial of off-the-shelf BKV-specific T-cells for the treatment of progressive multifocal encephalopathy (PML) was recently published in the New England Journal of Medicine.
We are also working on:
- Comprehensive analysis of NK cells and their receptors in cancer following hematopoietic stem cell transplantation using mass cytometry (CyTOF) and transcriptome profiling.
- Understanding mechanisms of NK immune evasion and using gene editing tools ot target checkpoints to enhance NK effector function
Anil Sood, M.D.
Professor, Department of Gynecologic Oncology and Reproductive Medicine
Co-Director, Ovarian Cancer Moonshots Program
Director, Blanton-Davis Ovarian Cancer Research Program
Vice Chairman, Department of Gynecologic Oncology and Reproductive Medicine
Co-Director, Center for RNA Interference and Non-Coding RNA
Dr. Sood received his M.D. at University of North Carolina (Chapel Hill, NC). He completed his residency at University of Florida - Shands Teaching Hospital (Gainesville, FL) in Obstetrics and Gynecology and was a Fellow in Gynecologic Oncology at University of Iowa Hospitals and Clinics (Iowa City, IA).
Sood Laboratory Research:
My research focuses on mechanisms of cancer invasion and metastasis in ovarian and other cancers. Specifically, my research is focused in three main areas:
1) effect of neuroendocrine stress hormones on ovarian cancer growth and progression
2) development of novel anti-vascular therapeutic approaches
3) development of new strategies for in vivo siRNA delivery.
We are also interested in understanding the effects of platelets on tumor growth. Our lab utilizes a wide range of in vitro and in vivo assays to study the topics described above.
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 Lab 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.
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.,
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.
Professor, Departments of Melanoma Medical Oncology and Immunology
Director, Department of Solid Tumor Cell Therapy
Dr. Yee completed his medical degree in Canada, residency at Stanford and an oncology fellowship at the Fred Hutchinson Cancer Research Center/ UW in Seattle. He was appointed Professor in 2009. In 2013, he was recruited to MD Anderson Cancer Center as a CPRIT established investigator and director of Solid Tumor Cell Therapy. He is an elected member of the American Society of Clinical Investigators, recipient of Clinical Translational Scientist Award from Burroughs Wellcome Fund and Damon Runyon Cancer Research Foundation, co-Leader of the Stand Up to Cancer- Immunotherapy Dream Team and Member of the Parker Institute for Cancer Immunotherapy.
Yee Laboratory Research:
His research over the last 20 years pioneered a form of ACT known as endogenous T cell (ETC) therapy which sources T cells from the peripheral blood. Using enabling technologies in engineering, microfluidics and cell sorting, together with discoveries in T cell biology, Dr. Yee demonstrated it was feasible to routinely isolate and expand antigen-specific memory T cells for the treatment of patients with cancer including melanoma, sarcoma, pancreatic, breast, and ovarian cancer. His lab has performed several first-in-human adoptive cell therapy studies and converges multidisciplinary approaches in bioengineering, metabolism, molecular immunology and cellular biology to develop immunotherapy strategies and adoptive cellular therapy, in particular, as a treatment modality for patients with malignant diseases. Translational and basic research studies in the Yee Lab include T cell memory, hypoxia, mouse models of pancreatic cancer and antigen discovery. He also has a machine that goes ‘ping’ (a clinical grade MEMS-based microfluidics cell sorter).