Michael Andreeff, M.D., Ph.D.
Department of Leukemia
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
Dr. Andreeff’s group has worked extensively on drug resistance in hematopoietic malignancies and breast cancer and developed or co-developed several new therapeutic agents including the novel triterpenoids CDDO and CDDO-Me and Bcl-2- , XIAP- , surviving-, MEK- and HDM2- inhibitors. Over the last decade, his group has made major contributions to the understanding of micro-environment-mediated drug resistance and developed strategies to exploit the underlying mechanisms for the treatment of hematopoietic and epithelial malignancies. His group reported the role of bone marrow-derived multipotent mesenchymal stromal cells (MSC) In tumor stroma formation and developed therapeutic strategies based on this discovery.
Robert C. Bast, Jr., M.D.
Department of Translational 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 trainees would be welcome include:
- 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 downregaulated 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.
- 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.
- 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.
Translational research in the Chandra Laboratory is directed towards leukemia and brain tumor therapeutics with an emphasis on oxidative stress, epigenetics and cell death. Understanding the mechanisms of action of novel therapies and devising therapeutic strategies that promote cell death is a major goal. The relationship between oxidative stress and cancer progression, as driven by oncogenes, is another major focus of the lab. Dr. Chandra also directs the ON (Optimizing Nutrition) to Life Program, a clinical/translational program examining oxidative stress and caloric intake in pediatric cancer patients.
The advent of clinically relevant, pharmacological targeting of constitutively active oncogenic kinases has yielded cures for some cancers such as chronic myeloid leukemia (CML). However in other malignancies, targeting of oncogenic kinases has been less successful, or resistance to targeted therapies has been particularly problematic. My research has delineated how oxidative stress stemming from oncogenes such as BCR-ABL1, which causes CML, activates a targetable set of genes. This provides new opportunities for treatment of refractory oncogenic kinase driven malignancies. The lab is currently
studying FLT3+ acute myeloid leukemia and EGFRvIII expressing glioblastoma in addition to CML.
We are actively developing new therapies and combinatorial strategies for leukemias and brain tumors, which respectively represent the most common and deadly cancers in children. Classes of agents we have studied include the proteasome inhibitors and epigenetically targeted agents such as the histone deacetylase inhibitors. Woven into these studies is a role for oxidative stress and its impact on efficacy. The chromatin modifying enzyme, LSD1 (lysine specific demethylase 1) is a drug target we are pursuing in adult and pediatric brain tumors. Using epigenetically targeted agents to modulate sensitivity to immunotherapies is of interest.
The lab is also studying how diet can be wielded as a means of modulating redox. We built a freely accessible online cookbook (www.mdanderson.org/recipes) with nutrition tips to serve as a resources for patients, survivors and families. A research dietician is part of the lab and carries out clinical research in pediatric patients and survivors. We recently completed a personalized nutritional counseling to pediatric leukemia and lymphoma patients currently on steroids, since weight gain is a common problem during this time. We examined oxidative stress in these patients as a biomarker of diet and exercise and are exploring effects on cellular epigenetics. Oxidative stress has been implicated as a mechanism of action for many of the comorbidities seen in cancer survivors, including cardiotoxicity stemming from anthracycline exposure, and increased risk of cancer and obesity related metabolic diseases. Through energy balance (diet and exercise) interventions, we hope to improve quality of life in pediatric cancer survivors.
Giulio Draetta, M.D., Ph.D.
Institute for Applied Cancer Science
Department of Genomic Medicine
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.
A rotation in the Draetta lab will provide a unique opportunity to train with an academic research scientist that truly understands the challenges and opportunities that surround an effective translation research program. His lab is currently composed of only ten members, which will ensure that you will receive personalized guidance and training directly from Dr. Draetta.
Genomic Medicine is a vibrant department focused on identifying genetic alterations in human cancers using genomics and bioinformatics and elucidating their function in sophisticated disease models. The Department is currently composed of the laboratories of Drs. Chin, DePinho, Draetta and Futreal. The Department is located in the newly constructed South Campus Research Building 4 and is equipped with state-of-the-art sequencing, cell and molecular biology laboratories. Genomic Medicine also works closely with and draws on the experience of the scientists at the IACS. Genomic Medicine has a weekly lab meeting in which all labs participate, which creates a collegial environment of cross discipline science.
Currently Dr. Draetta’s research efforts are focused on identifying genetic elements that lead to melanoma, glioblastoma and pancreatic cancer. Patients with these aggressive lethal cancers currently have few effective therapeutic options. An in-depth understanding of the signaling mechanisms in these cancers is needed to allow the rational development of effective targeted therapies. MD Anderson and specifically the Draetta Lab are uniquely positioned to conduct translational research due to ready access to patient samples, a strong interdisciplinary research community, cutting edge technology and the drive to rapidly translate research discoveries into improved patient care.
In collaboration with IACS, Dr. Draetta’s lab has developed a functional genomics screening platform to identify context-specific targets, where lineage, genetic and microenvironmental influences are carefully controlled. This novel approach is transformative because it will allow for the rapid identification of multiple targets, which will be validated under in vivo conditions and will provide candidate therapeutic targets and associated biomarkers. Specifically, libraries of genetic-elements of interest (either cDNAs or shRNAs) are introduced into genetically defined target cells that are either freshly isolated from patients’ tumors or derived from normal cells engineered to express various signature mutations. These cells are then orthotopically injected into mice and in vivo tumorigenicity is determined. A unique aspect of this platform allows for the specific genetic elements driving or suppressing tumor latency to be identified and prioritized for target validation. This novel platform will provide opportunities to rapidly evaluating hundreds of potential cancer targets simultaneously.
I direct a combined basic and translational laboratory focused on inflammation and selected other molecular aspects of melanoma directed toward development of novel therapeutics. I have two major areas funded to (1) develop a nanoparticle gene therapy using a novel tumor suppressor cytokine (IL-24) and (2) test inducible nitric oxide synthase (iNOS) as a marker of poor prognosis in melanoma tumors and also as a target for therapy in project #3 of the MD Anderson SPORE in Melanoma, for which I am also the overall Director.
The role of iNOS and other inflammatory mediators in melanoma is a major focus of current grant applications pending review.
Three faculty actively work in my laboratory and provide mentoring on a constant basis; they also work on melanoma drug and neutraceutical development, melanoma immunity, and molecular biology of melanoma genetic subclasses. Also, two postdoctoral fellows are studying basic molecular aspects of inflammation dysregulation in cancer. As well, I currently support two graduate students, both from the MD/’PhD programs. Additional grants are awarded to my laboratory personnel, so that the entire program is well funded and rich with resources to provide a thriving environment for training of M.D./Ph.D. programs.
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. Currently, he is a Principal Investigator for 1 PO1, 1RO1 and 1 DOD BCRP. In addition, Dr. Hung is a Project Leader for two MDACC Specialized Programs of Research Excellence (SPOREs) in Breast (also a Co-PI), and Ovarian Cancer and Program Leader for MDACC CCSG “Cell Biology and Signal Transduction” program. In 2008 (till 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.
TRIUMPH Melanoma Project Title: Generate a response against cancer using combinations of targeted and immunotherapy.
Objective: Determine rational therapeutic approaches to treat patients with metastatic melanoma utilizing melanoma mouse models and/or patient blood and tissue samples.
Surgery and chemotherapy have long been considered standard of care for metastatic melanoma, however the response rates for those treatment modalities remain dismally low (about 10 – 12%). Two new therapeutic approaches for melanoma (immunotherapy and targeted therapy) are gaining critical acclaim and acceptance. We have had response rates of over 45% in some of our early studies with immunotherapy and targeted therapy. This being said, we are still in the process of determining why, for immunotherapy, some patients have remarkable and durable results while others do not. Also, we have seen amazing initial results for some targeted therapies with almost immediate resolution of symptoms and tumors. However, such results have not proven to be durable for most patients. Further study and rational combinations of immune agents as well as targeted therapies may be essential to gain the fullest potential of personalized therapies.
Adoptive T-cell therapy (ACT) has tremendous potential for the treatment of patients with advanced cancers. We have been successful in identifying a patient’s own cancer killing cells (T-cells) and expanding those tumor-reactive T-cells to large numbers in the lab. Once they have multiplied to therapeutic numbers, these cells are then reinfused back into the melanoma patient from whom they were harvested. This revitalized force of soldier cells have the potential to aggressively and effectively wipe out the tumors they encounter. This has been a major and exciting laboratory-to-clinic undertaking, and as mentioned above has allowed us to help many patients who had limited options. We are now looking very close at our survivors who have been very kind in offering us blood and/or tumor samples to examine in our lab. One very important laboratory project we have underway is to look closely at the T-cells that have survived which remain primed waiting to attack any future cancer. Our objective is to determine how these cells correlate with patient responses, and to use what we learn to make ACT better.
Targeted therapy focus
The treatment of melanoma is entering into a new era of personalized therapy based on an improved understanding of the molecular causes and diversity of these cancers. We have gained a more focused direction from our molecular studies which have shed new light on the strategies needed to facilitate the development of more effective personalized targeted cancer therapies. We have had success in using specific drug combinations to shut down pathways that have halted the progression of melanoma for patients with specific molecular characteristics, however finding methods to make these results long lasting will take concerted effort. In addition, gaining the data needed to have new drugs approved as standard of care is a time consuming, but worth-wild effort.
Combinations of the best of both genres
The rational combination of the two disciplines mentioned above, target therapy and immunotherapy, are expected to result in substantial gains for our patients. It is now possible to combine immunologic agents such as TIL, CpG, anti-CTLA4 Interferon alpha, Interleukin-II, anti-CD40, and anti-41BB. Notwithstanding, targeted therapeutic agents such as MEK and BRAF inhibitors have shown remarkable results for some patients. This is a very exciting time to be engaged in melanoma research.
My laboratory is currently involved in 5 areas of research, for identifying novel therapeutic strategies and prognostic markers for breast cancer based on the alteration in the G1/S checkpoint in tumor cells. Below I have summarized 2 of the translational projects in more detail.
- Investigation of the low-molecular-weight (LMW) forms of cyclin E as prognostic markers in breast cancer for routine use in the clinic.
- Delineation of how the alteration of cyclin E, a G1 cyclin, could lead to the tumorigenic phenotype and determination of the oncogenic potential of the altered forms of cyclin E in breast cancer.
- Inhibition of LMW forms of cyclin E as a therapeutic target.
- Examination of the in vivo and subsequent clinical feasibility of a novel treatment strategy designed to protect normal proliferating cells against the toxic effects of chemotherapeutic agents.
- Determination of whether the proteasome is the target of G1 arrest/growth inhibition mediated by farnasyl-transferase inhibitors and structurally related compounds.
Investigation of the LMW forms of cyclin E as potential prognostic markers for routine use in the clinic. My laboratory has made the novel observation that cyclin E is present and overexpressed as LMW isoforms in breast cancer cells and tumor tissues. In a retrospective analysis of tumor specimens from 395 breast cancer patients, we established the overexpression of the LMW forms of cyclin E to be a strong predictor of poor survival (Keyomarsi, et al. New England Journal of Medicine, 2002). The hazard ratio for breast cancer death for patients with overexpression of cyclin E was 10-fold higher than the hazard ratio we obtained using patients’ lymph node status. Based on preliminary findings in the laboratory, we are also evaluating the use of LMW cyclin E as a predictor of poor response to hormonal therapy and chemotherapy. Our long-term goal is that once patients with deregulated cyclin E expression are identified, they may then be singled out for tumor directed therapy with cyclin E as the target. In addition, we will work toward the routine use of cyclin E as a biomarker for breast cancer patients by development of assays, which can be readily performed in tumor pathology laboratories, nationwide.
Inhibition of LMW forms of cyclin E as a therapeutic target. We have 2 different approaches to target the LMW forms of cyclin E: a pharmacologic one and a molecular one.
The pharmacologic approach involves the identification of kinase inhibitors specific to LMW cyclin E/cyclin-dependent kinase 2 (CDK2) complexes by screening a library of 12,000 compounds using an in vitro kinase assay developed by the laboratory of Dr Laurent Meijer in Roscoff, France. After this screening, we will identify the candidate compounds that selectively inhibit the proliferation of LMW cyclin E–over expressing cell lines. These steps will be followed by preclinical testing of the candidate CDK2 inhibitors using xenografts in athymic mice. Lastly, we will initiate clinical trials with the most promising of the cyclin E/CDK2 inhibitor in combination with chemotherapy in metastatic breast cancer.
The molecular approach targets the mechanism responsible for generating the LMW forms of cyclin E. This approach involves inhibiting the generation of the LMW forms of cyclin E through upregulation of elafin. We have shown that elafin can eradicate xenograft tumor growth in vivo. Our long-term goal is to use the LMW cyclin E/CDK2 specific inhibitors and/or elafin to inhibit control progression of the cell cycle in cancer cells, thus limiting the ability of these cells to populate distant metastatic sites. The information gained through these studies may have tremendous clinical relevance for women with early stage and advanced breast cancer. We already know that cyclin E overexpression correlates with poor outcome and that no alternative treatment strategy can currently be offered to these patients with altered expression of cyclin E. We believe there is a need to develop novel treatment strategies that could target the altered forms of cyclin E. Consequently, our hypothesis is that the tumor-specific, hyperactive, LMW forms of cyclin E can be targeted differentially from the full-length cyclin E by novel CDK2 inhibitors and elafin. These inhibitors would then be used as targeted therapy for those breast cancer patients whose tumors overexpress the LMW forms of cyclin E to potentially improve long term patient outcome in this poor prognostic patient cohort.
The mission of the Kleinerman lab is focused on Ewing’s Sarcoma and Osteosarcoma (OS), and identifying novel therapeutic strategies for both cancers. I am internationally recognized for my scientific and clinical expertise in sarcomas, and for my successes in translational research. My 30-year career has focused on understanding the biology and mechanisms involved in the metastasis of OS to the lung and the pathways that control the vascular development in Ewing’s sarcoma. The goal is to develop new therapeutic approaches for the treatment of patients with OS and Ewing’s sarcoma. I have a long publication record in both OS and Ewing’s sarcoma research, in defining the molecular pathways that control tumor vascular expansion, and in the biologic characteristics that influence the metastatic potential of sarcoma cells to the lung.
In Ewing’s sarcoma I developed a unique transplant model to identify how BM cells contribute to the vascular expansion in Ewing’s sarcoma. Using this model we were the first to show that vasculogenesis in addition to angiogenesis was critical to the expansion of the Ewing’s tumor vasculature. I went on to show that the vasculogenesis process in Ewing’s is mediated by DSF-1 and VEGF165, and that the Notch signaling pathway (in specific DLL4), controlled the differentiation of BM cells into tumor vascular pericytes. I was the first to show that there is a shift in VEGF expression from membrane-bound VEGF189 to the soluble VEGF165, which is controlled by CAPER-α alternative splicing; and that EWS-FLI-1 regulates the neuronal suppressor gene REST which controls the vascular morphology.
In OS I also developed a nude mouse model of human OS lung metastases which has enabled me to demonstrate that Fas expression inversely correlates with the metastatic potential of osteosarcoma cells and that the upregulation of Fas expression results in tumor regression. I was the first to show that the metastatic potential of OS to the lung is linked to dysregulation of the Fas/FasL pathway. I identified therapies (gemcitibine, entinostat, IL-12, 9-nitrocamptothecin) that restored Fas expression in OS lung metastases and induced tumor regression mediated by the FasL+ lung microenvironment. I have demonstrated the efficacy of aerosol gene and aerosol chemotherapy against osteosarcoma lung metastases which led to the initiation of several clinical protocols in pediatrics. I pioneered the use of immunotherapy in children with osteosarcoma lung metastases, demonstrating that liposome-encapsulated Muramyl Tripeptide (MTP-PE) activated the tumoricidal properties of macrophages and prolonged the disease free survival in relapsed OS patients. I led the phase II trials which demonstrated that MTP-PE activated the patient’s immune response, significantly increasing both the disease-free and overall survival of patients with relapsed osteosarcoma of the lung. Success of the phase II trials led to a national co-operative group phase III trial, which demonstrated that combining liposomal MTP-PE with combination chemotherapy significantly prolonged the survival of newly diagnosed patients with osteosarcoma and decreased the death rate by 30% at eight years. This drug has now been approved by the European Medicine Agency. Thus I have a successful track record of translating preclinical laboratory investigations into clinical trials.
My laboratory is currently involved in several areas of research, for identifying novel therapeutic strategies and prognostic markers for pancreatic cancer (PCA).
- Investigation of the basis of PCA resistance to therapies. We recently compared gene expression profiles between PCA cell lines that are either sensitive or resistant to gemcitabine after gemcitabine treatments. We observed several genes that were elevated in all cells as well as genes elevated only in the resistant cells. Some of the elevated genes have functions that suggest they may be involved in the resistance. We will examine this hypothesis for each molecule using in vitro and in vivo studies in order to identify targets for therapeutic development.
- Developing technologies for treating PCA. We have previously identified several molecules that are autocrine regulators of the aggressive growth and metastasis observed in PCA. We are currently developing monoclonal antibodies to some of these targets. We are also conducting drug screens or optimizing lead compounds. Our goal is to develop useful therapies.
- Targeting PCA using nanoparticles or viruses. We are evaluating specific peptides with affinities for PCA cells as targeting moieties. We are also testing PCA specific gene promoters.
- Targeting the PCA tumor microenvironment. We are investigating interactions between PCA cells and cells of the tumor microenvironment including stellate, immune and vascular cells. We have observed important effects of these non-cancer cells on PCA tumors. We wish to exploit the microenvironment to treat PCA.
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.
Gordon B. Mills, M.D., Ph.D., was recruited to MD Anderson in 1994, where he holds the rank of Professor with joint appointments in Systems Biology, Breast Medical Oncology and Immunology; serves as chairman of the Department of Systems Biology; head of the section of Molecular Therapeutics and holds the Wiess Distinguished University Chair in Cancer Medicine. Dr. Mills is co-Director of the Kleberg Center for Molecular Markers and Director for the Gita and Ali Saberioon Molecular Markers building. This Center is responsible for developing personalized molecular medicine at MDACC. Dr. Mills has published extensively on the molecular analysis of cancer and currently serves as principal investigator or project investigator on many national peer review grants including NIH/NCI SPOREs and PPGs, Department of Defense, and Komen Foundation grants, and is a collaborator on multiple other national grants. Dr. Mills also holds more than 20 patents related to novel technologies and molecular markers and has co-founded an early diagnostics company. He currently sits on the scientific advisory boards of multiple companies and venture capital groups. Based on his expertise in technology development, he is the head of the MD Anderson Cancer Center Technology Review Committee.
Our laboratory studies how T cells mediate blood cytopenia by targeting hematopoietic progenitor cells in bone marrow failure disorders and how allogeneic T cells mediate the graft-versus-leukemia (GVL) effect, which maintains long term remission after allogeneic stem cell transplantation (SCT). The long-term goal is to improve our understanding of GVL mechanisms so that we can devise highly targeted immune therapies for hematological malignancies that do not increase graft-versus-host immunity, an often-lethal complication of SCT that lacks effective treatment. Our work is focused on five areas of basic and translational investigation:
- Our lab identified the PR1 9-mer peptide, derived from proteinase 3 (P3) and neutrophil elastase (NE), as an important HLA-A2-restricted leukemia-associated antigen (LAA) and we are conducting multiple PR1 vaccine studies, including a pivotal phase 3 multinational trial, and studies that combine adoptive cell therapy plus PR1 vaccination for acute and chronic myeloid leukemia (AML and CML, respectively). Thus far, the vaccine induces immune responses with minimal side effects and may induce long-term molecular remission in treatment-refractory leukemia patients.
- We have produced a T cell receptor (TCR)-like monoclonal antibody (mAb) that binds with high affinity to a conformational epitope of PR1/HLA-A2 called 8F4. The 8F4 mAb preferentially eliminates AML but not normal hematopoietic cells, potentially through a complement-dependent mechanism. In a xenogeneic mouse model, 8F4 eliminated human leukemia stem cells and significantly increased survival of treated animals. Thus, 8F4 is the first mAb that can eliminate human cancer stem cells in vivo. We are developing a fully humanized 8F4 mAb for clinical testing.
- We are studying whether P3 and NE might function as tumor-associated antigens in non-hematopoietic tumors that lack endogenous expression. P3 and NE are abundant throughout the body, particularly at inflammatory sites and in the cancer microenvironment, and they regulate inflammation after they are secreted by activated neutrophils. After cell uptake of soluble P3 and NE, we found that PR1 is cross-presented on HLA-A2 molecules on breast cancer cells. Furthermore, PR1-specific cytotoxic T lymphocytes (PR1-CTL) and 8F4 mAb mediate lysis of breast cancer co-incubated with soluble P3 or NE. These observations link two immune regulatory proteins, which are normally only expressed in neutrophils and are secreted after cell activation, with a specific adaptive immune response against the P3- and NE-derived PR1 peptide following cross presentation on the malignant cell. This new mechanism linking inflammation and innate immunity to adaptive anticancer immunity is under investigation in our laboratory.
- We identified a novel enzyme-independent inhibitory function of soluble and neutrophil membrane-bound P3 on T cell proliferation, a new mechanism linking inflammation, autoimmunity, and cancer immunity. High P3 concentrations completely and reversibly inhibit CD4 and CD8 T cell proliferation by blocking the cell cycle G1-S transition, and inhibition is blocked by autoantibodies to P3 (cANCA) from patients with systemic vasculitis. The role of P3 in regulating autoimmunity and in preventing anticancer immunity, including CD8 T cell immunity against the P3-derived PR1 peptide, is being investigated in mouse models and in humans.
- Our found PR1-CTLs are significantly increased in fetal cord blood (CB) compared to adult peripheral blood and we are studying mechanisms that lead to incomplete central tolerance to the PR1 self-peptide antigen. We discovered an absence of PR1 on thymic epithelial cells and only modest expression on cortical-medullary dendritic cells in human thymus. Relative low P3 and PR1 peptide expression in thymic tissue could prevent the deletion of developing PR1-specific T cells, which is a common mechanism resulting in negative selection. Nevertheless, the high PR1-CTL frequency of PR1-CTL in CB suggests they could be useful in the CB transplant setting as a source of naïve PR1-CTL that could be transferred after minimal ex vivo cell manipulation to patients as post-transplant adoptive T cell therapy of PR1-expressing leukemia. This hypothesis is being tested in a preclinical xenogeneic mouse model of GVL, and in the clinic with adoptively transferred CB-derived PR1-CTL.
The mission of the Myers lab is to alleviate the suffering due to head and neck cancers through research into the mechanisms of disease progression and translational studies of investigational therapeutics in head and neck tumor models.
Our group has developed orthotopic nude mouse models of i) oral tongue cancer, ii) thyroid cancer, and iii) salivary gland cancer, and with these models we have evaluated the efficacy and in vivo mechanisms of action of investigational agents including i) natural products, ii) conventional chemotherapy and iii) molecularly targeted agents.
We are currently using molecular profiling of cell lines sensitive or resistant to molecular targeted agents to determine i) biomarker profiles predictive of response and/or outcome; ii) signaling pathways that might be dys-regulated in resistant cell lines. The molecular profiling strategies that we are using include i) cDNA microarray, ii) miRNA arrays, iii) reverse phase lysate arrays and iv) cytokine and angiogenic factor profiling.
Investigation using these in vivo and in vitro models have also lead to exciting work examining the role of p53 mutation in head and neck squamous cell cancer, and cutting edge research in the field of Metabolomics. We are establishing the role of metabolism in tumorgenicity and drug resistance as well as identifying metabolic targets to improve treatment for patients with head and neck cancer.
We are also working with collaborators from Rice University on the optimization of drug delivery through nanovector coupling of conventional chemotherapeutic agents as well as molecularly targeted agents to i) gold nanoparticles, ii) single walled carbon nanotubes, and iii) gold nanorods.
In order to further understand the mechanisms of disease progression we are analyzing genomic and metabolomic changes present in head and neck cancer cell lines and primary tumor samples. This work includes a large-scale comprehensive genomic analysis of primary tongue tumor samples.
It is anticipated that through the use of these complementary approaches we will make incremental progress in identifying new treatments that will improve the survival and quality of life of patients with cancers of the head and neck region.
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.
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.
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.
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.
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.
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.
My research program in cancer research encompasses three main areas of research: 1) neuroendocrine effects on ovarian cancer growth and progression; 2) anti-vascular approaches in ovarian cancer; and 3) development of novel nanoparticles for systemic in vivo delivery of siRNA. The trainees in my research group are heavily involved in all of these projects, as evidenced by their publications.
Therapeutic Gene Silencing In Vivo Using RNA Interference. While many new therapeutic targets have been identified, it is not possible to target all of these with conventional approaches such as small molecule inhibitors due to several reasons including: 1) large structure (eg, p130Cas) that would be difficult to target with a small molecule inhibitor; 2) kinase-independent functions, 3) high content of disorder in the native state; 4) multiple structural domains with independent functions, and 5) structure not fully known. In essence, the dearth of structural information precludes an effective use of other rational drug-design approaches. Moreover, most small molecule inhibitors lack specificity and can be associated with intolerable side effects. Similarly, while monoclonal antibodies have shown promise against specific targets such as VEGF, their use is limited to either ligands or surface receptors. The inability to target many novel, but promising targets with other approaches prompted us to utilize RNA interference (RNAi). Use of short interfering RNA (siRNA) as a method of gene silencing has rapidly become a powerful tool in protein function delineation, gene discovery, and drug development. The promise of specific RNA degradation has also generated much excitement as a possible therapeutic modality, but in vivo siRNA delivery has proven difficult. We have recently developed strategies for systemic siRNA delivery that allow therapeutic targeting of these and other proteins that would otherwise not be “drugable”. This strategy relies on highly efficient delivery of short interfering RNA (siRNA) systemically using a neutral nanoparticle. In proof-of-concept studies, we have targeted several genes that are critical for driving tumor growth and progression using this technology and demonstrated both in vivo gene silencing and therapeutic efficacy using orthotopic models of ovarian and other cancers. This work has been published in Cancer Cell, Nature Medicine, and Journal of the National Cancer Institute. Based on guidance from the FDA, we are conducting formal toxicology studies in anticipation of a first-in-human phase I trial with this novel therapeutic method. Our goals are now to develop highly targeted delivery methods for siRNA and non-coding RNAs.
Anti-Vascular Approaches in Ovarian Cancer. A major problem in management of ovarian cancer is metastasis. The progressive growth of primary tumor and metastases is dependent on an adequate blood supply (angiogenesis). Despite improvements in surgery and chemotherapy, the mortality rates in women with advanced ovarian carcinoma have remained largely unchanged. Targeting endothelial cells that support tumor growth is particularly promising because these cells are thought to be genetically stable and, therefore, less likely to accumulate mutations that would allow them to develop drug resistance. Vascular endothelial growth factor (VEGF) plays a critical role in neovascularization and consequent ovarian cancer growth and progression. Our findings demonstrate that a novel approach (high-affinity VEGF decoy receptor, VEGF Trap) for VEGF blockade is highly effective in combination with taxane chemotherapy in preclinical murine models and we have initiated a Phase I/II clinical trial as a part of the M. D. Anderson Ovarian Cancer SPORE grant. However, we recognize that despite the initial response rates to VEGF-targeted therapy, most patients eventually develop progressive disease. Therefore, new anti-angiogenic approaches are needed. We have completed a series of studies to provide a better understanding regarding the tumor vasculature over the last 5 years and some of the highlights include: 1) demonstration of the complexity of tumor vasculature in that a fraction of the vasculature in ovarian cancers is directly lined by tumor cells; 2) identification of gene differences in endothelial cells from tumor vasculature compared to normal ovarian endothelial cells; 3) development of novel metronomic chemotherapy approaches; 4) identification of mechanisms underlying VEGF-resistance; 5) clinical and functional characterization of novel angiogenesis targets including Src, focal adhesion kinase, PDGF-R, EphA2, and EphB4; 6) identification of new signaling pathways that allow pericytes to regulate endothelial cell survival in the tumor vasculature; and 7) combinatorial approaches for anti-vascular effects including the role of dual receptor (EGF-R and VEGF-R) targeting. These and other avenues constitute fertile areas for further research.
Neuroendocrine Modulation of Cancer Growth and Metastasis. Clinical studies have indicated that stress, chronic depression, social support, and other psychological factors can influence cancer onset and progression. Environmental and psychosocial processes initiate a cascade of information processing pathways in the central nervous system (CNS) and periphery, which subsequently trigger fight-or-flight stress responses in the autonomic nervous system (ANS) or defeat/withdrawal responses produced by the hypothalamic-pituitary-adrenal (HPA) axis. The adverse effects of chronic stress and associated hormones on the immune system have been known for a long time. However, the effects of these hormones on non-immune mechanisms of tumor growth and progression have not been well characterized. My laboratory made the novel observation that stress hormones can have direct effects on ovarian cancer cells via beta-adrenergic receptors and promote angiogenesis, tumor growth and progression. We have demonstrated direct modulation of pro-angiogenic cytokines and other metastasis-promoting genes such as FAK by key components of the sympathetic nervous system such as catecholamines. We have characterized these factors in pre-clinical and clinical settings and multiple publications have come out of this work including papers in Nature Medicine and Nature Reviews Cancer. Our ongoing work in this area of research is focused on dissecting the underlying pathways involved in cancer progression by neuroendocrine hormones using both in vitro and in vivo approaches that will be validated in human samples. Our long-term goal is to perform intervention studies to block the effects of stress biology on tumor growth. These strategies may include behavioral as well as pharmacological interventions.
My laboratory functions as a bridge to connect basic cancer research to important issues in cancer patient care. The long term goal of my research is to determine the molecular mechanisms of initiation, progression, metastasis, and therapeutic resistance of various types of cancers, with an emphasis on breast cancer. We are currently studying the involvement of ErbB2 receptor overexpression, 14-3-3 zeta overexpression, PTEN-loss, deregulation of cell signaling pathways in breast cancer. We are also developing strategies for early intervention of ER negative breast cancer.
- We previously found that PTEN-loss in breast cancer confers Herceptin-resistance (Cancer Cell, 6: 117, 2004, cited > 600 times). We recently developed strategies for overcoming Herceptin-resistance that have led to efficacious Phase I/II clinical trials. We are exploring different rationally designed, targeted therapeutics for treating human cancers using various preclinical animal models.
- My team identified 14-3-3z as a biomarker for selection of high-risk DCIS patients for treatment at early stages of breast cancer, while saving low-risk patients from ablative clinical procedures. This line of research also provided critical targets for intervention of the deadly transition from DCIS to IBC. We are currently investigating how 1433z overexpression induces breast cancer metabolic deregulation, chronic inflammation, and their contribution to breast cancer progression. These studies will identify new targets for intervention of breast cancer progression.
- Recently, we found that receptor tyrosine kinase signaling and Src activation can drive initiation and progression of ER- breast cancer. We are developing strategies targeting these pathways to prevent ER- breast cancer in women with mammary atypia. This translational research is supported by a Susan Komen Promise grant and will move to clinical trials.
- The recent new areas of interest in my lab include, but not limited to, molecular imaging of breast cancer progression, breast cancer brain metastasis, microRNA function in breast cancer therapeutic resistance and metastasis, epigenetic deregulation in early stage breast cancer, interactions of cancer cells and their activated stroma in cancer progression.