Congratulations to Dr. Stephanie Watowich (Department of Immunology) and Dr. Khandan Keyomarsi (Department of Experimental Radiation Oncology) on receiving a Cancer Prevention Institute of Texas (CPRIT) Individual Investigator Award for the project titled "Targeting neutrophil elastase as a novel therapy for metastatic breast cancer" in February 2018.
CPRIT TRIUMPH Faculty
James P. Allison, Ph.D.
Professor and Chair, Department of Leukemia
Vivian L. Smith Distinguished Chair in Immunology
Director, Parker Institute for Cancer Research
Executive Director, Immunotherapy Platform at MD Anderson Cancer Center
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 MDACC. 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 MDACC 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. Broaddus earned his Ph.D. in Cancer Biology and Immunology at the MD Anderson UTHealth Graduate School and his M.D. at UTHealth McGovern School of Medicine (Houston, TX). He completed post-graduate training in Anatomic Pathology at Baylor College of Medicine (Houston, TX).
Broaddus Laboratory Research:
Our lab is primarily focused on the study of the molecular pathogenesis of endometrial cancer, the most common gynecological cancer in women. Current projects in the lab are examining the molecular differences between aggressive and non-invasive endometrial cancers, gene methylation patterns in endometrial cancer, and the characterization of novel genes important in endometrial cancer. Other projects in our lab are identifying novel molecular biomarkers to help stratify ovarian cancer patients into different treatment and prognostic groups as well as molecular diagnostics of solid tumors and the incorporation of specific molecular diagnostic tests into clinical practice.
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. Chandra received her PhD 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. 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.
Elizabeth A. Grimm, Ph.D.
Professor, Department of Melanoma Medical Oncology
Waun Ki Hong Distinguished Chair in Translational Oncology
Deputy Division Head for Research Affiairs, Division of Cancer MEdicine
Dr. Grimm earned her PhD in Microbiology and Immunology from the UCLA School of Medicine.
Grimm Laboratory Research:
Dr. Grimm's research interests are divided into two major areas: (1) the fundamental cancer biology related to cytokine expression and inflammation in the maintenance of growth and apoptosis resistance pathways, which are based on her findings of endogenous constitutive nitric oxide in production in the tumor cells of patients with the worst prognoses; and (2) translational studies developing new therapies and validating prognostic markers in human melanoma. Her research in the 1980s at the NCI on human cytokines, particularly IL-2, led directly to its development as an approved agent for melanoma therapy. More recently, in experiments designed to reveal the mechanisms of IL-2 resistance which occurs in the majority of patients, the research in Dr. Grimm's lab has led to a focus on carcinogenic inflammation, which is associated with melanoma expression of various deleterious inflammatory markers, particularly inducible nitric oxide synthase (iNOS). Most recently, iNOS is proposed as a marker of poor prognosis as well as a target for therapy, with validation studies underway in her laboratory. Dr. Grimm hypothesizes that the molecular effects of iNOS produced nitric oxide (NO) and NO-driven reactive nitrogen species (RNS) directly modify critical growth and apoptosis proteins, resulting in reversible support inhibition of apoptosis.
Mien-Chie Hung, Ph.D.
Professor and Chair, Department of Molecular and Cellular Oncology
Vice President for Basic Research
Director, Center for Biological Pathways
Ruth Legett Jones Distinguished Chair
Director, Breast Cancer Basic Research Program
Mien-Chie Hung, Ph.D. is the Ruth Leggett Jones Distinguished Chair, Distinguished Teaching Professor, and Professor and Chair of the Department of Molecular and Cellular Oncology. He received his undergraduate and graduate degrees from the National Taiwan University in Taiwan and his Ph.D. from Brandeis University in Massachusetts. He was also trained as a postdoctoral fellow in Whitehead Institute/MIT. Dr. Hung is a basic scientist with a translational vision. Since he became an independent researcher in 1986, his laboratory has been well funded by extramural funding agencies including NIH and DOD. In 2008 (to present), he was appointed as the Director of Center for Biological Pathways at the MDACC to coordinate biological pathway studies in cancers through entire institution (the Center for Biological Pathways has amassed more than 130 faculty members from 42 departments).
Dr. Hung is internationally recognized for his work on signaling transduction pathways of tyrosine kinase growth factor receptors, such as epidermal growth factor receptor (EGFR) and HER-2/neu, and molecular mechanisms of oncogenes, including transformation and tumorigenesis. His group made a critical breakthrough in showing that the transmembrane tyrosine kinase receptor EGFR can translocate into the nucleus from the cell surface to stimulate cell proliferation and to induce resistance to anti-cancer therapy. This paradigm-shift concept revolutionizes cell biology of receptor tyrosine kinase and paves a novel avenue for designing next generation of anti-cancer therapy.
Most recently, Dr. Hung’s group revealed a novel mechanism that could link inflammation, obesity, diabetes and cancer, which provides a new way to develop obesity-induced cancer and diabetes. Dr. Hung’s laboratory has had a long commitment to developing effective gene therapy for breast, ovarian and pancreatic cancers, by identifying genes suitable for cancer therapy (E1A and BIKDD), developing gene delivery systems (cationic and neutral liposomes) and designing cancer-specific expression vectors, which enhance therapeutic efficacy and reduce any potential side effect during commonly used therapies. Dr. Hung was the first to show that the adenovirus type 5 E1A gene has antitumor activity in HER2/neu-overexpressing cancer cells in 1992, contrary to the originally and widely held belief that it was an oncogene. Studies on E1A as an anti-cancer gene have received national and international acclaim. In 1996, Dr. Hung collaborated with Dr. Hortoabgyi to bring the E1A gene into the first ever gene therapy trial for breast and ovarian cancer. Since then, multiple trials for E1A gene therapy in breast, ovarian and head and neck cancers have been completed (Clin Cancer Res 10:2986, 2004, Head Neck 24:661, 2002, Human Gene Ther 12:1591, 2001, Clin Cancer Res 7:1237, 2001 and J Clin Oncol 19:3422, 2001). He also developed a pancreatic cancer-specific expression vector to drive a potent mutant Bik gene, which is in process of moving into human clinical trials soon with his clinical colleagues.
Hung Laboratory Research:
The Hung laboratory is currently studying three themes in cancer research:Discovery of novel functionality of epidermal growth factor receptor (EGFR) family which might provide useful insight to understand cancer formation and developmentIdentification of crosstalks of signal pathways/networks in cancer cells and tumor microenvironment which could potentially predict resistance to target therapy and development of marker-guided targeted therapy which will effectively treat cancer patientsUnderstanding mechanism of immune checkpoint therapy and develop novel immunotherapies.
Kelly Hunt, M.D.
Professor and Chair, Department of Breast Medical Oncology
Hamill Foundation Distinguished Professorship in Honor of Dr. Richard G. Martin Sr
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:
Patrick Hwu, M.D.
Professor and Chair, Department of Melanoma Medical Oncology
Division Head, Division of Cancer Medicine
Chair, Department of Sarcoma Medical Oncology
Distinguished Chair, Sheikh Mohammed Bin Zayed Al Nahyan
Co-Director, Center for Cancer Immunology Research
Dr. Patrick Hwu is a tumor immunologist focused on the areas of vaccines, adoptive T-cell therapies, and immune resistance. His research and clinical efforts have led to insights and advances in the understanding of the interactions between tumors and the immune system, and the development of cellular therapies. He is the principal investigator on several NIH R01 translational immunotherapy grants, and other peer-reviewed grants. Several novel, ongoing clinical trials have resulted based on his group’s work, which include a trial of T-cells modified with chemokine receptor genes to enhance their migration to the tumor. Most recently, his preclinical studies have focused on combinations of immune checkpoint blockade and T-cell therapy, as well as rational combinations of targeted therapies and immunotherapies. Both of these concepts are being moved into the clinic to improve treatment outcomes for our patients.
Dr. Hwu earned his medical degree from the Medical College of Pennsylvania in Philadelphia. Following his service as a house officer in Internal Medicine at The Johns Hopkins Hospital, he completed a fellowship in oncology at the National Cancer Institute, where he continued to work for 10 years as a Principal Investigator leading tumor immunology studies. He was recruited to MD Anderson Cancer Center as the first Chairman of the Department of Melanoma Medical Oncology in 2003. He has served as Associate Director of the Center for Cancer Immunology Research since 2004. In addition, he has been Chair of the Department of Sarcoma Medical Oncology since June 2012. Most recently, he accepted the appointment of Head of the Division of Cancer Medicine, March 4, 2015. In recognition of his outstanding contributions to cancer research, Dr. Hwu has held endowed positions since joining the institution. He currently holds the Sheikh Mohammed Bin Zayed Al Nahyan Distinguished University Chair at MD Anderson Cancer Center.
Hwu Laboratory Research:
Significant advances in our understanding of the immune response against cancer have allowed us to design rational immune therapies for patients. My laboratory is focused on the translation of basic immunologic concepts from the laboratory to the clinic. We have found that some patients with metastatic cancer can be successfully treated with infusions of tumor-reactive T-cells. We are currently investigating methods to improve these therapies, by studying T-cell proliferation, survival, and trafficking using murine models as well as human T-cells.
Khandan Keyomarsi, Ph.D.
Professor, Department of Experimental Radiation Oncology
Hubert L. and Olive Stringer Professorship in Medical Oncology
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 5 areas of research, which fall into translational and basic research categories:
- Investigation of the low-molecular-weight (LMW-E) forms of cyclin E as prognostic markers in breast cancer for routine use in the clinic.
- Inhibition of LMW forms of cyclin E as a therapeutic target in combination therapy for triple negative breast cancer.
- Delineation of how the alteration of cyclin E, a G1cyclin, could lead to the tumorigenic phenotype and determination of the oncogenic potential of the altered forms of cyclin E in breast cancer.
- Determination of the mechanism of action of intracellular elastase and its inhibitor elafin in tumorigenesis and subsequent metastasis.
- Examination of mechanisms of action and resistance to CDK4/6 inhibitors in ER +breast cancer patients.
Eugenie Kleinerman, M.D.
Professor, Department of Pediatrics and Department of Cancer Biology
Mary V. and John A. Reilly Distinguished Chair
Eugenie S. Kleinerman, MD 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. 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 my laboratory is to understand the molecular mechanisms of breast tumor progression and metastasis. Our major interests include regulatory RNAs and deubiquitnating enzymes. We have played a major role in establishing the current models of non-coding RNA regulation of epithelial-mesenchymal transition, metastasis, and therapy resistance. Moreover, we discovered the deubiquitinases for key cancer proteins; some of these deubiquitinases are promising therapeutic targets.
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 MDACC, 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.
Jeffrey N. Myers, M.D., Ph.D., F.A.C.S.
Professor, Department of Head and Neck Surgery
Alando J. Ballantyne Distinguished Chair of Head and Neck Surgery
Director or Translational Research, Division of Surgery
Director of Research, Department of Head and Neck Surgery
Deputy Chair for Academic Programs, Department of Head and Neck Surgery
Dr. Myers earned his Ph.D. in Biochemistry and his M.D. at the University of Pennsylvania School of Medicine (Philadelphia, PA). He completed his residency in Otolaryngology-Head and Neck Surgery at the University of Pittsburgh School of Medicine (Pittsburg, PA) and a fellowship in Head and Neck Surgery at University of Texas MD Anderson Cancer Center (Houston, TX). Dr. Myers leads a basic and translational research program and his primary research interests are in the role of p53 mutation in oral cancer progression, metastasis, and response to treatment.
Myers Laboratory Research:
Squamous cell carcinoma, tongue neoplasms, p53 gain of function mutations
Dr. Navin earned his PhD 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 PhD 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.
Jack A. Roth, M.D.
Professor, Thoracic & Cardiovascular Surgery
Chief, Section of Thoracic Molecular Oncology, Department of Thoracic and Cardiovascular Surgery
Bud S. Johnson Distinguished Clinical Chair
Dr. Roth earned his M.D. from Johns Hopkins University (Baltimore, MD), where he completed his clinical internship and Clinical Residency in Surgery. Additionally, he completed a Clinical Residency at UCLA School of Medicine (Los Angeles, CA), where he also served as Chief Resident in the Division of Thoracic Surgery and in the Division of General Surgery. Dr. Roth completed a Research Fellowship at UCLA Center for the Health Sciences in the Division of Surgical Oncology. He served as senior investigator and head of the Thoracic Oncology Section in the National Cancer Institute’s Surgery Branch before joining the University of Texas M. D. Anderson Cancer Center(UTMDACC) in 1986 as professor and chair of the Department of Thoracic and Cardiovascular Surgery. He serves as founding director of the W. M. Keck Center for Innovative Cancer Therapies and holds academic appointments in UTMDACC’s Department of Molecular and Cellular Oncology and the Department of Cardiothoracic and Vascular Surgery at The University of Texas Medical School at Houston. While at the NCI, Dr. Roth completed the first randomized clinical trials of neoadjuvant chemotherapy for squamous carcinoma of the esophagus and open lung biopsy in immunocompromised patients with diffuse pulmonary infiltrates. At UTMDACC, Dr. Roth has initiated and acted as the principal investigator of the first gene therapy trials for lung cancer. Dr. Roth has spearheaded the development of institutional multidisciplinary protocols in thoracic oncology and was the principal investigator of the first randomized trial showing survival benefit with neoadjuvant chemotherapy in stage IIIA resectable lung cancer.
Among his landmark achievements, Dr. Roth was principal investigator for the first tumor suppressor gene therapy clinical trials approved by the National Institutes of Health Recombinant DNA Advisory Committee and the U.S. Food and Drug Administration. Approval for those historic protocols was based on his demonstrating feasibility and efficacy through laboratory and preclinical studies. His team showed that restoration of function for a single normal tumor suppressor gene could mediate regression of human cancers in vivo, helped identify and characterize a number of novel tumor suppressor genes on chromosome 3, and found that systemic delivery of tumor suppressor genes using a nanoparticle vector could effectively treat disseminated human lung cancer in animal models. These observations led Dr. Roth and colleagues to initiate the first clinical trial using nanoparticles to deliver genes systemically. Cancer gene therapy developed in his laboratory became the first gene therapy to be approved for human use. In addition to being an international leader in developing gene therapy for lung and other cancers, he has trained a new generation of outstanding surgical oncologists and laboratory researchers who are applying his philosophy of excellence throughout the world.
Numerous major grants supporting the Roth-directed translational research include an NCI SPORE Grant in lung cancer, the first awarded to a UTMDACC investigator that is shared by faculty at UTMDACC and The University of Texas Southwestern Medical Center. The joint collaboration has been renewed four times. Roth was responsible for establishing the Keck Center for Innovative Cancer Therapies to serve as an institute without walls to coordinate targeted therapy studies among UTMDACC investigators. He has contributed to more than 480 articles in peer-reviewed journals and 110 book chapters, and been awarded nearly 50 U.S. and foreign patents with another 50 pending. He has received numerous awards including the Lucy Wortham James Basic Research Award, Society of Surgical Oncology; The Best Doctors in America Award for over 18 consecutive years; Award of Excellence, 32 nd Annual Congress, Japan Society for Cancer Therapy; the Charles Moetel Lecture, Mayo Clinic; the Gordon Hamilton-Farley lecture, British Association for Cancer Research and British Society for Surgical Oncology; Elaine & Gerald Schuster Distinguished Visiting Lecturer, Harvard Medical School; Inaugural Glick Lecturer, Johns Hopkins School of Medicine; the Claggett Award Lecture, Mayo Clinic; Fellow American Association for the Advancement of Science, and The Otis W. and Pearl L. Walters Faculty Achievement Award in Clinical Research.
Roth Laboratory Research:
Gene therapy, molecular biology of lung cancer, targeted cancer therapy, nanotechnology, translational research and application. The major goals of our research effort are to identify critical genes and their products in the lung carcinogenesis pathway and their mechanism of action and to develop novel cancer treatment and prevention strategies targeted to specific genetic abnormalities, the biological hallmarks of cancer, and signaling pathways in lung cancer cells. Our current research activities are focused on understanding the molecular mechanisms of novel tumor suppressor genes recently identified in the human chromosome 3p21.3 region where the genomic and genetic abnormalities are frequently found in a wide spectrum of human cancers including lung and breast cancers and on exploring their therapeutic applications for lung cancers by nanoparticle-mediated gene transfer in vitro, in animal models, and in human clinical trials.We are also interested in using advanced genomics and proteomics approaches to identify signature genes and proteins that are involved in oncogenic and tumor suppressor pathways and associated with sensitivity phenotypes of lung cancer cells to novel experimental therapeutics. Our research activities emphasize an understanding the mechanisms of drug resistance by exploring combination treatment strategies for enhancing therapeutic efficacy and overcoming the drug resistance. Our current laboratory and translational research activities are summarized below.
1)Functional Characterization of 3p21.3 Tumor Suppressor Genes.
By collaborating with Dr. John Minna at The UT Southwestern Medical Center, Dallas through our Lung Cancer SPORE program, we have studied the effects of 3p21.3 genes on tumor cell proliferation and apoptosis in human lung cancer cells by recombinant adenovirus- and plasmid vector-mediated gene transfer in vitro and in vivo.We found that forced expression of several wild-type 3p21.3 genes include FUS1,101F6, RASSF1, and NPRL2 significantly inhibited tumor cell growth by induction of apoptosis and alteration of cell cycle processes in 3p-deficient NSCLC and SCLC cells and significantly suppressed tumor growth and progression in lung cancer mouse models. Our findings provided the first direct evidence for the tumor suppressing activities of 3p21.3 genes in vitro and in vivo and suggest that multiple contiguous genes in the critical 3p21.3 homozygous deletion region collectively function as a tumor suppressor region.
2) Development of Novel Vectors and Nanotechnology for Systemic and Targeted Delivery of Therapeutic Genes, siRNA, and Peptides and Molecular Imaging.
We developed Protamine-Adenoviral vector complexes (P-Ads) for efficiently delivering recombinant adenoviral vectors for treatment of human primary lung tumors and lung metastases by either systemic administration or by respiratory inhalation of the aerosolized P-Ad complexes.We developed numerous novel plasmid vectors and DOTAP:Cholesterol- and gold-nanoshell-based nanoparticle delivery systems for tumor-selective and high-efficient delivery of therapeutic genes, siRNAs, and peptides for clinical cancer therapy and for non-invasive molecular imaging and monitoring of gene expression, bio-distribution, and therapeutic efficacy.
3) Studies of therapeutic efficacy and molecular mechanisms of combination treatment with TUSC2 (FUS1)-nanoparticle and Molecular Targeted Therapeutic Drugs.
We investigated the therapeutic effects of combination treatments with multifunctional DOTAP:Cholesterol (DC)-FUS1 nanoparticles and small molecule tyrosine kinase inhibitors (TKIs), such as EGFR inhibitors gefitinib/erlotinib and ZD6474, Src inhibitor dasatinib and KX2-391, and MEK inhibitor AZD6244, AKT inhibitor MK2206, for enhancing the therapeutic potency of TKIs and overcoming drug resistance in lung cancer cells in vitro and in vivo, We found that that reactivation of wild-type FUS1 by FUS1 nanoparticle-mediated gene transfer into FUS1-deficient and TKI-sensitive or resistant lung cancer cells significantly sensitized their response to TKIs treatment by synergistic induction of apoptosis and inhibition of activities of multiple oncogenic kinases such EGFR, MEK, AKT, PDGFR, c-Kit, Src, and Met in EKFR/ERK/AKT in vitro and in lung cancer mouse models. Our findings suggest a combination treatment with DC-FUS1-nanoparticles and TKIs may be a useful strategy for more effectively treating lung cancer and overcoming drug resistance by simultaneously activating apoptosis and blocking oncogenic kinase signaling pathways.
4) Translational Application of Intravenous Gene Therapy with Tumor Suppressor TUSC2(FUS1)-Nanoparticles for Advanced Lung Cancer.
We conducted the first in-human systemic gene therapy clinical trial that involves intravenous nanoparticle-delivery of the tumor suppressor gene TUSC2 (FUS1). We showed evidence of uptake of the gene by human primary and metastatic tumors, vector-specific transgene RNA expression, expression of the gene product, specific alterations in TUSC2-regulated pathways, and clinical efficacy. Thirty-one patients with recurrent lung cancer were treated with escalating doses of intravenous DOTAP:cholesterol (DC) nanoparticles encapsulating the TUSC2 expression plasmid. RT-PCR analysis detected high TUSC2 plasmid expression in 6 of 7 post-treatment tumor specimens but not in pretreatment specimens. TUSC2 protein staining in pretreatment tissues was low or absent compared with intense TUSC2 protein staining in post-treatment tissues. RT-PCR gene expression profiling analysis of apoptotic pathway genes showed significant post-treatment changes. Five patients achieved stable disease (2.6-10.8 months, including 2 minor responses). One patient with stable disease had a metabolic response on positron emission tomography (PET) imaging. We have shown for the first time that a functioning TSG can be delivered intravenously to human cancer cells using a nanoparticle vector, express high levels of mRNA and protein in cancer cells in the primary tumor and distant metastatic sites, alter relevant pathways in the cancer cell, and mediate clinically beneficial anti-tumor activity.
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.
Dihua Yu, M.D., Ph.D.
Professor, Department of Molecular and Cellular Oncology
Hubert L. & Olive Stringer Distinguished Chair in Basic Sciences
Deputy Chair, Department of Molecular and Cellular Oncology
Dr. Yu earned her M.S. in Neuro-Cardio Physiology and her M.D. at Capital University of Medicine (Beijing, China). She went on to earn her Ph.D. in Molecular Biology and Cancer Biology from MD Anderson UTHealth Graduate School of Biomedical Sciences.
Yu Laboratory Research:
My laboratory functions as a bridge connecting basic & translational cancer research to important issues in cancer patient care. In the new era of personalized cancer therapy, several new challenges are emerging. Our research is focused on tackling these new challenges. First, we are dissecting mechanisms of resistance to targeted- and immuno- therapies, and designing counteracting strategies to make patients respond better to anti-cancer therapies. Second, we are decoding cancer metastasis, especially brain metastasis, and designing effective therapies based on mechanistic understanding. Third, we are developing early detection, prevention, and intervention strategies for breast cancer and colon cancers. For example, we are using 2D and three-dimensional (3D) cell culture models and various preclinical animal models, including cancer cell xenograft, patient-derived xenograft (PDX), transgenic, and knockout mouse models, as well as tissue and plasma specimens from patients. Our recent research areas also include, but are not limited to, stem cells and breast cancer initiating cells, molecular imaging of cancer progression, dysregulation of i) metabolism, ii) tumor microenvironment; iii) epigenetic modifiers, and iv) immune responses, and their roles in cancer progression, metastasis, and resistance to therapies.