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Last Updated: 09/03/20

Dana-Farber/Harvard Cancer Center Kidney Cancer SPORE

Beth Israel Deaconess Medical Center

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

PRINCIPAL INVESTIGATOR CONTACT INFORMATION

David F. McDermott, M.D.
Chief, Medical Oncology
Beth Israel Deaconess Medical Center
Leader, Kidney Cancer Program
Dana-Farber/Harvard Cancer Center
Professor of Medicine
Harvard Medical School
330 Brookline Ave, Boston, MA 02215
Tel: 617-667-0226
Fax: 617-667-0230

William G. Kaelin, Jr., M.D.
Professor of Medicine
Harvard Medical School
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

OVERVIEW

The Dana-Farber/Harvard Cancer Center (DF/HCC) Kidney Cancer Specialized Program of Research Excellence (SPORE) has been funded 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 Georgetown-Lombardi Cancer Center (GLCC) is 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 has served with Dr. McDermott as Director of the SPORE since 2014. Dr. Kaelin is a world renowned basic and translational investigator with longstanding interest in renal cancer and a leader within the DF/HCC community. Drs. McDermott and Kaelin report directly to Dr. Laurie Glimcher, Director of DF/HCC and President of DFCI. 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 propose 3 Projects which address critical problems in kidney cancer and have translational components. They focus on identifying effective strategies for targeting: HIF2α, the dominant oncogenic driver of clear-cell RCC (Project 1), resistance mechanisms of standard therapies (Projects 2-3, DRP 17), novel immune checkpoint pathways (Project 3) and rare kidney tumor types (e.g. NF2 mutated and translocation RCC, DRP 18 and 17). 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: Targeting HIF2 and VHL Synthetic Lethal Interactions in Kidney Cancer

Project Co-Leaders:
William Kaelin (Basic Co-Leader)
Sabina Signoretti (Basic Co-Leader)
Toni Choueiri (Clinical Co-Leader)

Inactivation of the VHL tumor suppressor gene is the initiating genetic event in most clear cell renal cell carcinomas (ccRCCs) and increases the abundance of HIF2α, which drives ccRCC growth. HIF2α inhibitors are active against some, but not all, VHL-/- ccRCCs in preclinical models. In the last funding cycle we and others showed that HIF2 inhibitors (e.g. PT2977) have promising antitumor activity in pretreated ccRCC patients. While the efficacy signal seen with PT2977 has justified the launch of a pivotal trial that could lead to its regulatory approval, some ccRCC patients fail to respond to HIF2 blockade. Moreover, the patients that do respond to PT2977 monotherapy eventually relapse in most cases. We need biomarkers that identify patients who are likely to respond to HIF2α inhibitors (predictive biomarkers) and to understand the mechanisms of resistance to such agents. We need new therapeutic targets in kidney cancer. Ideally, drugs against these new targets would be active as single agents and could be combined with existing agents, with the combinations increasing response rates and decreasing therapeutic resistance.

Two genes are synthetically lethal with one another when mutation of either gene alone is tolerated but inactivation of both genes causes cell death. This paradigm has been validated in the clinic with the activity of PARP inhibitors against BRCA1 mutant tumors. In our last funding cycle, we discovered that VHL and CDK4/6 have a synthetic lethal relationship. Moreover, we showed that the hyperdependence of VHL-/- ccRCC cells was NOT driven by HIF2. In keeping with the latter, we showed that CDK4/6 inhibitors were active against VHL-/- ccRCCs, irrespective of their HIF2 dependence, and enhanced the activity of PT2977 against HIF2-dependent VHL-/- ccRCC.

In aim 1 of this proposal we will conduct a phase 1/2 trial of the CDK4/6 inhibitor abemaciclib, alone and in combination with PT2977. In aim 2 we will search for additional genes that are synthetic lethal with VHL. We will leverage our ability to do synthetic lethal screens in both human cells and drosophila cells as a means of identifying genetic interactions that are likely to be robust. In aim 3 we will use genetic approaches to identify the mechanisms by which cells become resistant to HIF2 inhibitors. This aim could eventually yield new ways of predicting which ccRCC patients will respond to HIF2 inhibitors as well as new ways to circumvent resistance.

PROJECT 2: Optimal Targeting of the PD-1/PD-L1 Pathway in MRCC

Project Co-Leaders:
Catherine Wu (Basic Co-Leader)
Michael Atkins (Clinical Co-Leader)

Anti-PD-1-based therapies have transformed the management of advanced renal cell carcinoma (RCC), leading to durable responses in a subset of patients. Despite this progress, the optimal therapeutic strategy (anti-PD-1 monotherapy versus dual checkpoint inhibition and dual checkpoint inhibition versus VEGF and PD-1 inhibition) for individual patients remains unclear, and too many patients still do not receive durable benefit from any of the PD-1 blockade-based therapies. Moving forward, the critical challenges are (i) how to best match a patient to an immunotherapy regimen, and (ii) understanding the key drivers and resistors of anti-RCC immunity following PD-1 blockade. Our unique access to a rich collection of samples from several front-line PD-1-blockade-based clinical trials and our comprehensive immunopathology and immunogenomics tool-kit for deeply dissecting the biologic features tumor cells and the immune microenvironment, uniquely position our group to address these challenges. To achieve the next paradigm shift in the treatment of patients with RCC, we hypothesize that an improved understanding of the expression state of RCC cells and their immune microenvironment at baseline provides critical information that will uncover targets for novel therapies and will rationally guide PD-1 blockade-based combinatorial therapy. We aim to clarify first-line therapy decisions by developing biomarkers for durable benefit from anti-PD-1 monotherapy, nivolumab/ipilimumab and axitinib/pembrolizumab combination therapy using existing tissue collections, and then explore/confirm the value of these markers in the context of prospective phase III trials comparing the nivolumab/ipilimumab combination to either nivolumab monotherapy or axitinib/pembrolizumab. Ultimately, our efforts to establish a predictive model of durable benefit will help determine the appropriate RCC population to receive PD-1/CTLA-4 or PD-1/VEGF blockade, as well as unveil those patients who receive equal benefit from anti-PD-1 monotherapy or who require a different therapeutic approach. Moreover, we will use complementary analyses across patient samples to comprehensively characterize immune cell composition and functional state, determine target tumor antigens, and specific TCRs that mediate an effective anti-tumor response in RCC with the goal of ultimately developing novel immunotherapy approaches that enhance or induce specific and effective anti-tumor immunity. This work has the potential to optimize the application of currently effective anti-PD-1-based therapies for patients with advanced RCC and to provide new and effective immunotherapy approaches for those destined to not benefit optimally from current regimens.

PROJECT 3: HHLA2 as a Therapeutic Target in RCC

Project Co-Leaders:
Gordan Freeman (Basic Co-Leader)
David McDermott (Clinical Co-Leader)

While immune checkpoint inhibitors (ICI) have revolutionized the treatment of many cancers, including metastatic clear cell renal cell carcinoma (ccRCC), the development of agents that overcome resistance to anti-PD-1/PD-L1 based therapy represents a critical unmet need for ccRCC patients. We have shown that the B7 family member HERV-H LTR-associating 2 (HHLA2) is expressed in the majority of ccRCC and recently have discovered an inhibitory receptor (KIR3DL3) for HHLA2. Monoclonal antibodies that selectively block the HHLA2/KIRDL3 interaction, which we call the HHLA2 Inhibitory Pathway (HIP), could be an important means to enhance anti-tumor immune responses. In this proposal, we will study the expression of HHLA2 and it receptors in kidney cancer on tumor cells and immune cells and the relationship of HHLA2 and PD-L1 expression on tumors cells. Using clinically annotated specimens from clinical trials of patients with ccRCC on anti-PD-1 therapy, we will determine whether HHLA2 expression is associated with lack of response to PD-1 therapy. We will elucidate the regulatory pathways that are similar and different between HHLA2 and PD-L1 to better understand the expression of these immune checkpoints in kidney cancer and how their expression may change over the course of tumor progression and selection pressures. We will identify the optimal reagents for activating T cells and NK cells through the HHLA2:KIR3DL3 pathway in both in vitro and in vivo models. Our results will direct the selection of humanized blocking antibodies of HHLA2 Inhibitory Pathway that will move into primate toxicity and human Phase I clinical trials during year two of this grant.

Administrative Core

Co-Directors:
David McDermott
William Kaelin

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.

DF/HCC Kidney Cancer SPORE Biostatistics and Bioinformatics

Director:
Paul Catalano

The Dana-Farber/Harvard Cancer Center (DF/HCC) SPORE in Kidney Cancer Biostatistics and Bioinformatics 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 bioinformatic 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 bioinformatic 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 biostatistical and bioinformatic consulting to SPORE researchers. Organizing biostatistical and bioinformatic expertise as a shared resource core is a cost-effective approach to ensure that collaboration is readily available to SPORE investigators and an effective strategy to guarantee a high degree of integration among projects with interrelated analytic goals and needs. The development of new statistical and computational methodologies for cancer research has resulted in an expanded role for the statistician, bioinformatician and computational biologist in the research process and a higher standard for what constitutes acceptable scientific evidence in a study. Biostatisticians and computational biologists are professionally committed to staying on top of these developments and apply their expertise to check assumptions, assure appropriate use, and interpret results and limitations — a challenge beyond what can reasonably be expected of translational investigators.

DF/HCC Kidney Cancer SPORE Tissue, Acquisition, Pathology and Clinical Data

Co-Directors:
Rupal S. Bhatt
Toni Choueiri
Othon Iliopoulos

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 Dana-Farber/Harvard Cancer Center (DF/HCC) hospitals, including the Dana-Farber Cancer Institute and Brigham and Women’s Hospital (DFCI/BWH), the Beth Israel Deaconess Medical Center (BIDMC), and the Massachusetts General Hospital (MGH). 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 and Bioinformatics 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 animal models. These services include: laser capture microdissection (LCM) to provide ultra-pure tumor samples; performance of routine immunohistochemistry (IHC) and multiparametric 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 multiplex IF stains using computer-assisted image analysis; development of novel RCC models.

Developmental Research Program (DRP)

Co-Directors:
David McDermott
Michael Atkins

To ensure a continual renewal of high-quality scientific endeavors in the DF/HCC Kidney Cancer SPORE and to fund efforts that will complement or enhance the overall quality of the DF/HCC Kidney Cancer SPORE. In general, the DRP has funded established investigators. Based on our review, we will be mindful of including more junior investigators. This Program will rely on the infrastructure created by the Administrative, Evaluation, and Planning Core (Admin Core) to:

  1. Solicit applications and/or identify novel kidney cancer research projects.
  2. Evaluate these projects for funding.
  3. Fund innovative developmental projects.
  4. Re-evaluate projects for possible transition into full project status.
  5. Evaluate the success of the program.

Career Enhancement Program (CEP)

Co-Directors:
William Kaelin
Othon Iliopoulos

The investigators assembled in the DF/HCC Kidney Cancer SPORE have a substantial record in mentorship and enhancement of junior faculty working in the kidney cancer field (detailed below). The goal of the Career Enhancement Program (CEP) of our SPORE is to build upon this record and continue a formal process for the identification, selection, funding, and mentoring of individuals pursuing careers in the study of the basic, translational, and clinical aspects of kidney cancer. This Program will rely on the infrastructure created by the Administrative, Evaluation, and Planning Core (Admin Core) to:

  1. Solicit CEP Award Applications
  2. Evaluate Applicants and Select Awardees
  3. Conduct CEP Evaluation and Review
  4. Mentor CEP Awardees and promote Career Progress