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Last Updated: 10/10/18

Kidney Cancer SPORE

Dana-Farber/Harvard Cancer Center

Principal Investigators:
David F. McDermott, M.D.
William G. Kaelin, Jr., M.D.

PRINCIPAL INVESTIGATOR CONTACT INFORMATION

David F. McDermott, M.D.
Beth Israel Deaconess Cancer Center/Dana-Farber/Harvard Cancer Center
Director, Biologic Therapy and Cutaneous Oncology Program
Division of Hematology/Oncology
375 Longwood Ave.
Masco Building, Room 412
Boston, MA 02215
Tel: 617-632-9250
Fax: 617-632-9260
Email: dmcdermo@bidmc.harvard.edu

William G. Kaelin, Jr., M.D.
Professor of Medicine
Dana-Farber Cancer Institute and Harvard Medical School
Investigator
Howard Hughes Medical Institute
450 Brookline Avenue, Mayer 457
Boston, MA 02215 USA
Tel: 617-632-3975
Fax: 617-632-4760
E-mail: william_kaelin@dfci.harvard.edu

INTRODUCTION

It is estimated that 61,560 new cases of kidney and renal pelvis cancer will be diagnosed in the United States in 2015. Kidney cancer is one of the 10 most common cancers and is diagnosed in both men and women at all ages. Approximately 14,080 patients will lose their life to this disease annually. In 2003, the National Cancer Institute the Dana Farber/ Harvard Cancer Center a Kidney Cancer SPORE grant (Specialized Programs of Research Excellence) enabling world renowned clinical investigators, scientists and researchers to work collaboratively to make significant advances in the diagnosis and treatment of kidney cancer.

In Spring 2015, the National Cancer Institute (NCI) awarded a five-year grant renewal to DF/HCC for its continued leadership of this multi-center kidney cancer research consortium which includes Beth Israel Deaconess Medical Center (BIDMC), Dana-Farber Cancer Institute (DFCI), Harvard Medical School (HMS), Harvard School of Public Health (HSPH), Brigham and Women’s Hospital (BWH), Massachusetts General Hospital (MGH), Boston Children’s Hospital (BCH), the Whitehead Institute at Massachusetts Institute of Technology (MIT), and Georgetown-Lombardi Comprehensive Cancer Center (GLCCC).

The Kidney SPORE is overseen by co-Principal Investigators David F. McDermott, MD, Leader of the Dana Farber/Harvard Cancer Center Kidney Cancer Program and Dr. William Kaelin, a laboratory scientist at DFCI and Associate Director for Basic Science in the DF/HCC. The SPORE in kidney cancer is a highly integrated program focusing on tumor genetics, minimally invasive therapy, and immune immunotherapy for renal cell carcinoma. This SPORE approaches the therapeutic intervention of this disease from several different angles, including angiogenesis inhibition, immune modulation, and inhibition of specific cancer-related molecular pathways. A notable accomplishment of this SPORE is its identification of a gene whose inactivation accounts for approximately one-third of Wilms tumors, a common pediatric tumor.

The Kidney Cancer SPORE fosters collaborations among the national experts in renal cancer, and generates resources and research opportunities which otherwise would not exist for the scientific community. The leadership of the Kidney Cancer SPORE engages experts from throughout the United States and abroad through the Kidney Cancer Association, Society for the Immunotherapy of Cancer, the Cytokine Working Group or through collaborations in industry-sponsored trials. The SPORE offers its expertise and facility as a resource for correlative biomarkers for a number of nationally conducted clinical trials and also conducts national meetings on topics focused on different aspects of translational research in kidney cancer

OVERALL ABSTRACT

This grant represents a renewal of the SPORE in Kidney Cancer from the Kidney Cancer Program of Dana-Farber/Harvard Cancer Center (DF/HCC). The DF/HCC Kidney Cancer SPORE has been funded for two cycles since 2003. DF/HCC is comprised of the following institutions: Beth Israel-Deaconess Medical Center (BIDMC); Dana- Farber Cancer Institute (DFCI); Harvard Medical School; Harvard School of Public Health; Brigham and Women’s Hospital; Massachusetts General Hospital (MGH); and Children’s Hospital of Boston. In addition to the institutions in the DF/HCC, the Whitehead Institute at Massachusetts Institute of Technology and Georgetown-Lombardi Cancer Center (GLCC) are collaborating institutions in this grant. The DF/HCC Kidney Cancer SPORE has its administrative base at the BIDMC.

Dr. David McDermott, who has led the DF/HCC Kidney Cancer Program and SPORE since 2012 is joined as SPORE Director by Dr. William Kaelin, a laboratory scientist at DFCI and Associate Director for Basic Science in the DF/HCC. The DF/HCC Kidney Cancer SPORE has a broad and deep talent base and there is extensive institutional commitment. We take advantage of a large patient population and cutting edge technologies that are available to us as part of DF/HCC. We have developed 4 Projects which address critical problems in kidney cancer and have translational components. They focus on identifying effective strategies for targeting: HIF2a, the dominant oncogenic driver of clear-cell RCC (Project 1), angiogenesis inhibitor resistance mechanisms, which undermine the most commonly applied therapies (Project 2) and improving the therapeutic index of agents targeting the mTOR (Project 3) and immune checkpoint pathways (Project 4). The projects are supported by three Cores — an Administrative Core, a Biostatistics and Computational Biology Core, and a Tissue Acquisition, Pathology and Clinical Data Core. We also have a highly successful Career Development Program that selects talented physician scientists and mentors them to independence as well as a Developmental Projects Program that generates new ideas for the SPORE in the future. The existence of the SPORE has provided opportunities and incentives to extend basic science and clinical research ideas into the translational realm and facilitated the entry of young, as well as some seasoned, investigators into the kidney cancer field where they have made major contributions.

PROJECT 1: SMALL MOLECULE HIFa INHIBITORS FOR TREATMENT OF RENAL CELL CARCINOMA

William G. Kaelin, Jr. M.D. — Basic Co-Leader (DFCI)
Keith Flaherty, M.D. — Clinical Co Leader (MGH)
Toni Choueiri, M.D. — Co-Investigator (DFCI)
Sabina Signoretti, M.D. — Co-Investigator (BWH)

There are several forms of kidney cancer. The most common form is referred to as clear cell renal carcinoma. The initiating event in most clear cell renal carcinomas is the inactivation of a protein called the VHL tumor suppressor protein. Loss of the VHL protein leads to increased activity of several proteins that belong to the HIF protein family. We showed before that increased activity of one of the HIFs, called HIF2, promotes the growth of clear cell renal carcinomas. HIF2 is a so-called transcription factor and controls the activity of over 100 genes in clear cell renal carcinomas, including the gene that governs the production of vascular endothelial growth factor (VEGF). It has been well established that drugs that block VEGF are helpful for treating clear cell renal carcinomas but they are not curative. We believe that targeting HIF2 itself will be far more effective than simply blocking one of the many genes it activates (such as VEGF). We are working closely with Peloton Therapeutics, which has developed a drug that blocks HIF2 function in laboratory models. In aim 1 and 2 we will conduct a clinical trial to determine if this drug can, indeed, block HIF2 activity in man and, if so, whether this leads to clinical benefit for patients with clear cell renal carcinoma. In aim 2 we will also develop new ways of monitoring HIF2 activity in clinical samples. In aim 3 we will ask whether blocking HIF2 function can, as expected, enhance the antitumor effects of VEGF inhibitors against clear cell renal carcinomas in mouse models of this disease. We recently made the unanticipated discovery that thalidomide, which has become an important drug for the treatment of a cancer called multiple myeloma, works by earmarking two transcription factors (called IKZF1 and IKZF3) for destruction. This gives us hope that we could, in time, discover drugs that likewise mark the HIF2 transcription factor for destruction. We will attempt to identify such drugs in aim 4. If successful, such drugs should markedly enhance the actions of drugs, such as the Peloton drug, that block HIF2 function. In addition, combining two drugs that inhibit HIF2 in two different ways should decrease the emergence of clear cell renal carcinoma cells that are resistant to therapy (since they would now have to circumvent two forms of attack on the same target).

PROJECT 2: HDM2 AS A THERAPEUTIC TARGET IN RCC

James Mier, M.D. — Basic Co-Leader (BIDMC)
Michael B. Atkins, M.D. — Clinical Co-Leader (GU)
Rupal Bhatt, M.D. — Co-Investigator (BIDMC)
David Panka, Ph.D. — Co- Investigator (BIDMC)

Treatment with any of several VEGF receptor-targeted tyrosine kinase inhibitors (TKIs) results in prolonged disease stability or even regression in the majority of patients with metastatic renal cell carcinoma (RCC). This antitumor effect is generally transient and incomplete, however, due to the rapid development of drug resistance. This project emerged from our earlier work in RCC xenografts on the mechanisms of acquired TKI resistance. We observed that p53 activation was essential for a robust response to sunitinib. We also noted that the expression of p53-dependent genes was transient and down modulated with the onset of TKI resistance. Finally, we demonstrated that the concurrent administration of a drug that blocks HDM2- dependent p53 ubiquitylation and degradation prevented the development of TKI resistance. At least two potential mechanisms for this effect were documented, one of which involved in the induction of the E3 ligase Fbw7 and the degradation of the oncoprotein HIF-2alpha. Another potential mechanism by which HDM2 antagonists prevent TKI resistance is their ability to block the expression of hypoxia-driven chemokines such as SDF-1 (CXCL-12) and to prevent the influx of CD11b+/Gr-1+ myeloid-derived tumor suppressor cells (MDSC). In this project, we propose to carry out a Phase I/Ib clinical trial examining a combination of sunitinib with the HDM2 antagonist CGM097 (Novartis). This trial will have a 20 patient expansion cohort in which the administration of the HDM2 antagonist will be delayed in half of the patients. Tumor biopsies will be performed on these patients (half of which will be receiving sunitinib alone and half the drug combination at the time of biopsy) to assess the effects of treatment on p53 activation and MDSC and Treg trafficking. We will examine the effects of MDSC depletion on treatment outcome in murine RCC models and will determine if targeting the SDF-1 receptor (CXCR4) with the CXCR4 inhibitor AMD11070 prevents MDSC recruitment and the onset of TKI resistance as effectively as HDM2 blockade. Finally, we will assess the effects of HDM2 blockade on the expression of IL-8, FGF, and other factors previously implicated in the development of TKI resistance

PROJECT 3: TARGETING mTOR DEPENDMENT MECHANISM IN CLEAR CELL RENAL CARCINOMA

David Sabatini, Ph.D. — Basic Co-Leader (Whitehead Institute)
Toni Choueiri, M.D. — Clinical Co-Leader (DFCI)
David Kwiatkowski, M.D. — Co-Investigator (BWH)
Elizabeth Henske, M.D. — Co-Investigator (BWH)

The mechanistic target of Rapamycin (mTOR) complex 1 (mTORC1) is a master regulator of cellular growth and metabolism. Two allosteric inhibitors of mTORC1, the rapalogs temsirolimus and everolimus, are FDA approved for renal cell carcinoma (RCC). However, despite the fact that mTORC1 appears to be activated in the majority of RCC, only a subset of patients derives significant clinical benefit from these agents. Currently there are no predictive biomarkers of treatment response to mTORC1 inhibitors in RCC. The recent TCGA analysis of RCC identified multiple genetic alterations that potentially result in constitutive activation of the mTOR pathway (seen in 8-17%, e.g. MTOR). This leads to our first hypothesis, that mutations in genes encoding critical proteins in the PI3K-mTOR pathway will be associated with clinical response to rapalog therapy in RCC. Recently several drugs have been developed that are ATP-competitive mTOR kinase inhibitors. This leads to our second hypothesis, that ATP-competitive mTOR kinase inhibitors will have benefit for patients who progress on rapalog therapy. CRISPR gene editing technology has recently been developed, and enables genome wide screens for enhancers of rapalog effects on cell growth. This leads to our third hypothesis, that a genome-wide CRISPR/Cas9 screen will identify genes that are essential for kidney cancer growth and/or confer synthetic lethality when combined with mTOR inhibition, thereby leading to an improved therapeutic strategy. Hence, our specific aims are: 1A: To identify genetic predictors of response to agents targeting the mTOR pathway in advanced RCC. 1B: To study mechanisms of resistance to mTOR inhibitors occurring in vivo in patients. 2: To conduct an mTOR-kinase inhibitor (MLN0128) trial in metastatic RCC patients who progressed on rapalog therapy, including genetic analysis and cell line development. 3A: To conduct genome-wide CRISPR/Cas9 screens to identify genes essential or conditionally essential upon mTOR inhibition in kidney cancer cells in vitro; to validate and prioritize these genes; and to determine the contribution of hit genes to tumor cell growth in vivo.

PROJECT 4: OPTIMAL TARGETING OF THE PD-1/PDL-1 PATHWAY IN METASTATIC RENAL CELL CARCINOMA

David F. McDermott, M.D. — Clinical Co-Leader (BIDMC)
Gordon Freeman, Ph.D. — Basic Co-Leader (DFCI)
Sabina Signoretti, M.D. — Co-Investigator (BWH)
Michael B. Atkins, M.D. — Co-Investigator (GU)

Advances in tumor immunology have led to a better understanding of the immunoinhibitory mechanisms (e.g. inhibitory ligands/receptors and regulatory T cells) that create a major barrier to effective anti-tumor immunity. One of the most critical pathways responsible for mediating tumor-induced immune suppression is the programmed death-1 (PD-1) pathway. While the early results seen with PD-1 pathway blocking antibodies (Abs) in cancer have been encouraging, further study is required to optimize their use in RCC patients. Preliminary correlative studies suggest that while tumor PD-L1 expression may increase the likelihood of benefit with anti-PD-1, it fails to identify all responders. Predictive biomarker development and validation will help to guide this approach to the proper patients (Aims 1 and 2). The application of PD-1 blockade in the treatment naïve setting may yield even better results and obviate the need for subsequent lines of therapy (Aim 2). Using a multi-faceted approach, this project will provide a better understanding of the mechanisms of action and resistance to PD-1 pathway blockade, thereby facilitating the development of effective combination regimens (Aims 2 and 3). We will study the impact of intra-tumoral heterogeneity on biomarker development through our unique collection of matched primary tumor and metastasis specimens in our SPORE Tissue Bank and samples obtained from two prospective clinical trials of patients receiving anti-PD-1 antibodies. Laboratory experiments will integrate novel Abs, engineered proteins and genetic tools including: 1) anti-PD-1, PD-L1, and PD-L2 monoclonal Abs for IHC of human tissues and long term treatment of mice; 2) whole-exome and transcriptome sequencing of both tumor and infiltrating T cells (TILs), which can be used to explore mechanisms of innate resistance, and 3) innovative murine models such as mice that conditionally lack PD-1 on specific cell types and reporter mice that enable FoxP3 visualization. This highly collaborative team of basic and clinical scientists brings together an exceptional collective expertise in RCC immunotherapy trials, the PD-1 pathway and tumor immunoregulation, which should facilitate the generation of clinically meaningful results.

CORE A: DF/HCC KIDNEY CANCER SPORE ADMINISTRATION

David F. McDermott, M.D. — Co-Leader
William G. Kaelin, Jr., M.D. — Co-Leader

The purpose of the Administration, Evaluation and Planning (Administrative) Core is to assure the coordination of the Dana Farber/Harvard Cancer Center (DF/HCC) Kidney Cancer SPORE components and to continue to provide oversight and leadership for the scientific, administrative and fiscal aspects of the SPORE. The Administrative Core allows for the provision of stimulating intellectual activities, organization of venues for planning future research through seminars and retreats, and the oversight of research and spending. Drs. McDermott and Kaelin, the SPORE Directors, are committed to the success of the SPORE and will personally monitor the progress of the Projects and Cores, oversee the Career Development and Developmental Research Programs, and oversee all other proposed activities. As both SPORE Directors and Leaders of the Kidney Cancer Program within the Dana-Farber/Harvard Center (DF/HCC), Drs. McDermott and Kaelin have the authority and resources to ensure the success of this SPORE. The Administrative Core of the DF/HCC Kidney Cancer SPORE will accomplish the goals of the SPORE by following six specific aims: 1) Monitor research progress and plan for the future, 2) foster collaborative research within and between SPOREs, 3) Integrate the DF/HCC Kidney Cancer SPORE into the structure of DF/HCC, 4) Provide necessary resources and fiscal oversight, 5) promote patient participation, particularly minorities, in Kidney Cancer research and treatment 6) Promote rapid dissemination of significant research findings and free and open communication and resource exchange between the DF/HCC SPORE and other institutions. As they have since early 2014, Drs. McDermott and Kaelin will provide the tools to foster collaborations between the institutions inside and outside of the SPORE, to leverage the considerable power of the SPORE in order to promote kidney cancer research.

CORE 1: DF/HCC KIDNEY CANCER SPORE BIOSTATISTICS

Paul Catalano, ScD — Core Director

The Dana-Farber/Harvard Cancer Center (DF/HCC) SPORE in Kidney Cancer Biostatistics and Computational Biology Core (Core 1) collaborates and provides consultation on all research activities within the SPORE including SPORE Projects, the Developmental Research and Career Development Programs, and other SPORE Cores - to ensure the highest standards of scientific rigor in areas of study design, data management and integrity, and data analysis and interpretation. The specific aims are to: 1. Provide biostatistical and computational biology expertise for the planning and design, conduct, analysis, and reporting of laboratory, genomic, animal, translational, clinical (including associated correlative studies), and epidemiological studies for SPORE Projects, Developmental Research and Career Development Program projects, and other SPORE Cores. 2. Provide consultation on all issues of data management and integrity, including data collection, storage, transfer and quality assurance, on statistical and computational biology software and programs, and on coordination of laboratory results with parameters and outcomes from clinical studies or clinical/translational research databases 3. Provide short-term biostatistics and computational biology consulting to SPORE researchers.

CORE 2: DF/HCC KIDNEY CANCER SPORE TISSUE, ACQUISTION, PATHOLOGY AND CLINICAL DATA

Sabina Signoretti, M.D. — Core Director (BWH)
Toni Choueiri, M.D. — Co-Core Director (DFCI)
Rupal Bhatt, M.D. — Co-Core Director (BIDMC)
Othon Ilioupoulos, M.D. — Co-Investigator (MGH)
Gupta Mamta, M.D. — Co-Investigator (BIDMC)
Michelle Hirsch, M.D. — Co-Investigator (BWH)
Chin-Lee Wu, Ph.D. — Co-Investigator (MGH)

The first and foremost goal of the Tissue Acquisition, Pathology, and Clinical Data (TAPCD) Core is to maintain and expand the existing repository for specimens, including tissues, blood and urine from patients with kidney tumors that have given consent to link their samples to clinical data. Included in this component are the collection, freezing, and storage of fresh samples of kidney cancer and paired non-tumor tissue; the collection, processing and storage of blood and urine; the identification and provision of samples of fixed tissues, including construction of tissue microarrays (TMAs) from biopsy and nephrectomy samples obtained from patients who have consented to allow analysis of these tissues. The caTissue system, which is the NCI caBIG's biorepository tool for biospecimen inventory management, is currently used to track specimens through every step of the requesting, shipping, and receiving process through the use of barcode technology.

Importantly, the TAPCD Core will continue to maintain a database of clinical data (CRIS) on all consenting RCC patients. The value of the database is enhanced by the use of standardized pathology review procedures and data collection procedures. The database and specimen tracking system provide an informatics link among the participating DF/HCC hospitals, including the Dana-Farber Cancer Institute and Brigham and Women’s Hospital (DFCI/BWH), the Beth Israel Deaconess Medical Center (BIDMC), Massachusetts General Hospital (MGH) and Children’s Hospital of Boston (CHB). This allows seamless sharing of specimen resources, linked to clinical outcome data, behind a secure data management system that is available to SPORE investigators at all participating institutions. The protection of patient confidentiality is guarded throughout the whole process, from specimen collection to use in research projects. The Biostatistics Core is and will continue to be responsible for assisting in the data analysis, data auditing and quality control.

Finally, TAPCD Core has provided and will continue to provide SPORE investigators a variety of services critical to successful molecular analysis of human kidney tumors as well as xenograft models. These services include: histopathologic review and quality control analysis of all tumor samples utilized in experimental studies; macrodissection of frozen tissue samples and slide microdissection of paraffin-embedded or frozen tissues to ensure high neoplastic cellularity for samples utilized in experimental studies; laser capture microdissection (LCM) to provide ultra-pure tumor samples; performance of routine immunohistochemistry (IHC) and immunofluorescence (IF) stains on human kidney cancers (TMAs or whole tissue sections); optimization and validation of antibodies to known and novel proteins for use in IHC and IF; analysis of a broad range of IHC and IF stains using computer-assisted image analysis; development of novel RCC models.

LEADERSHIP

David F. McDermott, M.D.

David F. McDermott, M.D.

Principal Investigator

Dr. McDermott is Director of the Biologic Therapy and Cutaneous Oncology Programs at Beth Israel Deaconess Medical Center. He is Leader of the Dana Farber/Harvard Cancer Center Kidney Cancer Program and Principal Investigator of the NCI Kidney Cancer SPORE grant. Dr. McDermott is a clinical investigator with a particular interest in therapies that enhance the immune response to cancer. He has contributed to the rational application of interleukin-2 and immune check point inhibitors (CTLA-4, PD-1 antibodies) for renal cell carcinoma and melanoma. He has worked with anti-angiogenic agents and targeted therapeutics for these malignancies. He is Director of the Cytokine Working Group which has been a major innovator in the field of solid tumor immunotherapy. Dr. McDermott is Associate Professor of Medicine at Harvard Medical School.

Dr. McDermott earned his medical degree from Cornell University Medical College, followed by residency in internal medicine and fellowship in hematology/oncology at Tufts/New England Medical Center. Dr. McDermott has served on the Program Committee for the American Society of Clinical Oncology as well as the Medical Advisory Board for the Kidney Cancer Association. He serves on the NCI Kidney Cancer Task Force.

William G. Kaelin, Jr., M.D.

William G. Kaelin, Jr., M.D.

Co-Principal Investigator

William Kaelin is a Professor in the Department of Medicine at the Dana-Farber Cancer Institute and at the Brigham and Women's Hospital, Harvard Medical School, where he currently serves as Associate Director, Basic Science, for the Dana-Farber/Harvard Cancer Center. He obtained his undergraduate and MD degrees from Duke University and completed his training in internal medicine at the Johns Hopkins Hospital, where he served as chief medical resident. He was a clinical fellow in medical oncology at the Dana-Farber Cancer Institute and later a postdoctoral fellow in the laboratory of David Livingston, during which time he was a McDonnell Scholar.

Dr. Kaelin is a member of the National Academy of Sciences, the Institute of Medicine, the American Society of Clinical Investigation and the American College of Physicians. He recently served on the National Cancer Institute Board of Scientific Advisors, the AACR Board of Trustees, and the Institute of Medicine National Cancer Policy Board. He is a recipient of the Paul Marks Prize for cancer research from the Memorial Sloan-Kettering Cancer Center; the Richard and Hinda Rosenthal Prize from the AACR; a Doris Duke Distinguished Clinical Scientist award; the 2010 Canada International Gairdner Award; ASCI’s Stanley J. Korsmeyer Award; the Scientific Grand Prix of the Foundation Lefoulon-Delalande; the Wiley Prize in Biomedical Sciences, and the Steven C. Beering Award.

A Howard Hughes Medical Investigator since 1998, Dr. Kaelin’s research seeks to understand how, mechanistically, mutations affecting tumor-suppressor genes cause cancer. His laboratory is currently focused on studies of the VHL, RB-1, and p53 tumor suppressor genes. His long-term goal is to lay the foundation for new anticancer therapies based on the biochemical functions of such proteins. His work on the VHL protein helped to motivate the eventual successful clinical testing of VEGF inhibitors for the treatment of kidney cancer. Moreover, this line of investigation led to new insights into how cells sense and respond to changes in oxygen, and thus has implications for diseases beyond cancer, such as anemia, myocardial infarction and stroke.