Dana-Farber/Harvard Cancer Center SPORE in Breast Cancer
Dana-Farber Cancer Center
Principal Investigator(s):
Kornelia Polyak, MD, PhD
Nancy Lin, MD
Geoffrey Shapiro, MD, PhD
- Principal Investigator(s) Contact Information
- Overview
- Project 1: Overcoming Breast Cancer Resistance to CDK4/6 Inhibition
- Project 2: Combination Immunotherapy Approaches to Overcome Therapeutic Resistance in HER2-Positive Breast Cancer
- Project 3: Improving Therapeutic Approaches for Breast Cancer Brain Metastases
- Project 4: Combined Use of Immunotherapy and Targeted Treatments for Triple Negative Breast Cancer
- Administrative Core
- Biostatistics and Computational Biology Core
- Biospecimen and Pathology Core
- Developmental Research Program
- Career Enhancement Program
- Institutional SPORE Website
Principal Investigator(s) Contact Information
Kornelia Polyak, MD, PhD
Professor of Medicine, Harvard Medicine
Dana-Farber Cancer Institute
44 Binney Street Mayer 228
Boston, MA 02115
Tel: (617) 632-2106
Fax: (617) 580-8490
Nancy U. Lin, MD
Associate Chief, Division of Breast Oncology, Susan F. Smith Center for Women’s Cancers
Director, Metastatic Breast Cancer Program
Dana-Farber Cancer Institute
Mayer 228
44 Binney Street
Boston, MA 02115
(617) 632-3800
Geoffrey Shapiro, MD, PhD
Senior Vice President, Developmental Therapeutics
Clinical Director, Center for DNA Damage and Repair
Professor of Medicine, Harvard Medical School
Dana-Farber Cancer Institute
Mayer 446
450 Brookline Avenue
Boston, MA 02215
(617) 632-4942
Overview
The Dana-Farber/Harvard Cancer Center (DF/HCC) SPORE in Breast Cancer seeks to improve the understanding and treatment of breast cancer, using innovative and highly translational approaches. The program consists of four projects, three cores, a developmental research program (DRP) and a career enhancement program (CEP).
Project 1: Overcoming Breast Cancer Resistance to CDK4/6 Inhibition
Project 2: Combination Immunotherapy Approaches to Overcome Therapeutic Resistance in HER2-Positive Breast Cancer
Project 3: Improving Therapeutic Approaches for Breast Cancer Brain Metastases
Project 4: Combined Use of Immunotherapy and Targeted Treatments for Triple-Negative Breast Cancer
Core A, the Administrative Core, is the epicenter of scientific, fiscal, and administrative oversight. It leads efforts in planning and communication, and houses the Patient Advocacy Committee. Core A will ensure that existing DF/HCC structures support the SPORE clinical and translational research efforts. Core B, the Biostatistics and Computational Biology Core, provides specialized expertise in biostatistics and management of genomic data. Core C, the Biospecimen and Pathology Core, maintains tissue and blood repositories, provides critical pathology services, and performs cutting edge assays for the SPORE projects. Core C also comprises the Immuno-Oncology Sub-Core. The DRP and CEP identify novel approaches to translational questions in breast cancer and support early career investigators.
Project 1: Overcoming Breast Cancer Resistance to CDK4/6 Inhibition
Project Co-Leaders:
Eric Winer, MD (Clinical Co-Leader)
Peter Sicincki, MD (Basic Co-Leader)
Project 1 brings together outstanding investigators to study mechanisms of resistance to CDK4/6 inhibitors. In estrogen receptor-positive breast cancer, we hypothesize that CDK2 hyperactivation is a cause of acquired resistance to CDK4/6 inhibitors. Preclinical work will be complemented by analysis of paired biopsies obtained prior to initiation of a CDK4/6 inhibitor and when resistance develops. In triple-negative breast cancer (TNBC), we will evaluate the possibility that lysosomal sequestration of CDK4/6 inhibitors limits their therapeutic efficacy. We will determine if this sequestration can be reversed by administering hydroxychloroquine in preclinical models and will also conduct a clinical trial of a novel CDK4/6 inhibitor combined with hydroxychloroquine in patients with TNBC. Finally, we aim to investigate the role of MAPK pathway upregulation in resistance in a clinical trial combining MAPK and CDK4/6 inhibition with hormonal therapy in patients with metastatic hormone receptor-positive/HER2-negative breast cancer and acquired CDK4/6 inhibitor resistance.
Project 2: Combination Immunotherapy Approaches to Overcome Therapeutic Resistance in HER2-Positive Breast Cancer
Project Co-Leaders:
Shom Goel, MD, PhD (Basic Co-Leader)
Ian Krop, MD, PhD (Clinical Co-Leader)
Recently it has become clear that HER2+ breast cancer (BC) is immunogenic. HER2 is a strong tumor antigen, and a proportion of HER2+ BCs harbor a lymphocytic infiltrate, which predicts for improved outcomes. In addition, anti-HER2 antibodies exert their effects in part by stimulating immune effector cells. Collectively, these facts provide rationale for testing immunotherapy in HER2+ metastatic BC. Our co-investigator Dr. Loi recently conducted a phase II study of trastuzumab and pembrolizumab (a PD-1 inhibitor) in patients with HER2+ metastatic BC (PANACEA). The study met its primary endpoint and thus provides proof-of-principle for the use of immunotherapy in HER2+ disease. However, only a small minority of patients benefited.
In Project 2, we will study two novel therapeutic approaches designed to further boost the anti-tumor immune response against HER2+ BC, including:
- the use of CDK4/6 inhibitors, given together with trastuzumab and PD-1 blockade; and
- the addition of PD-L1blockade and a 4-1BB agonist to chemotherapy and trastuzumab.
Both regimens are rationally designed, based on our preclinical data showing that these combinations markedly amplify anti-tumor immunity. In each Aim, we will perform a randomized, multicenter phase II clinical trial to determine the efficacy of these novel approaches and/or a “co-clinical trial” with mouse studies running in parallel to human trials. The animal experiments will be performed using our transgenic model of human HER2-driven mammary carcinoma (MMTV-rtTA/tetO-HER2) and will incorporate cutting-edge technologies to understand the mechanisms of activity, as well as detailed studies of resistance mechanisms (including next-generation sequencing and multiplexed immunofluorescent profiling of tumor tissue). The trials involve collection of tumor biopsies and blood samples. Ultimately, these studies will:
- characterize the immune landscape of advanced HER2+ BC in detail;
- determine whether either of the two novel approaches is an effective clinical strategy;
- establish cellular mechanisms of activity for each regimen; and
- explore mechanisms of therapeutic resistance.
This work may uncover new therapies that enhance immune responses against HER2-positive BC and significantly improve patient outcomes.
Project 3: Improving Therapeutic Approaches for Breast Cancer Brain Metastases
Project Co-Leaders:
Nancy Lin, MD (Clinical Co-Leader)
Jean Zhao, PhD (Basic Co-Leader)
Despite their potential clinical impact, existing preclinical models of breast cancer brain metastases (BCBM) have been limited, and the factors that influence BCBM growth are not well elucidated. To date, no systemic therapy has gained regulatory approval for the treatment of BCBM. Hence, this represents an area of unmet medical need. Preclinical investigations have suggested a role for at least two key pathways in the growth and maintenance of BCBM, including PI3K/PTEN/mTOR and cyclin D1/CDK4. The overarching goals of this project are to elucidate the roles of the PI3K/PTEN/mTOR pathway and the Cyclin D1/CDK4 pathway in the growth and development of BCBM, to dissect the basis of site-specific response/resistance to inhibitors of these pathways, to test the clinical utility of targeting these pathways in patients with BCBM, and to identify ways to predict and overcome therapeutic resistance, with the long-term goal of identifying more effective treatment and prevention strategies. To accomplish our aims, we have assembled a multidisciplinary team enabling close bi-directional collaboration between the laboratory and clinic. We will leverage our unique collection of patient-derived xenograft (PDX) models generated from human BCBM specimens, and genetically-engineered mouse models (GEMMs), combined with state-of-the art molecular pathology techniques.
In Aim 1, we will:
- test whether PTEN loss promotes the growth and maintenance of BCBMs, and evaluate the effects of genetic or pharmacologic restoration of PTEN function;
- evaluate brain-penetrant PI3K/mTOR inhibitors in preclinical models of BCBM and uncover potential mechanisms of site-specific resistance; and
- test the efficacy of combined PI3K/mTOR blockade in patients with HER2+ BCBM.
In Aim 2, we will:
- evaluate the efficacy of CDK4/6 inhibition, alone and in rational combinations;
- evaluate the efficacy and immuno-modulatory effects of CDK4/6 inhibitors, alone and in combination with immune checkpoint blockade and in varying genetic backgrounds; and
- explore the clinical efficacy of combined HER2 and CDK4/6 inhibition in patients with HER2+ BCBM.
Together, these studies will further our understanding of the pathophysiology of BCBM, strengthen our ability to overcome therapeutic resistance, and improve outcomes for patients with this disease.
Project 4: Combined Use of Immunotherapy and Targeted Treatments for Triple Negative Breast Cancer
Project Co-Leaders:
Geoffrey Shapiro, MD, PhD (Clinical Co-Leader)
Kornelia Polyak, MD, PhD (Basic Co-Leader)
Although several lines of evidence support the use of immunotherapy in triple-negative breast cancer (TNBC), the modest efficacy achieved in trials suggests that the immunosuppressive microenvironment cannot be overcome by PD-1/PD-L1 blockade alone. To improve outcomes, this project will investigate the immunologic effects of two classes of targeted breast cancer therapies, poly (ADP-ribose) polymerase (PARP) and BET bromodomain (BBD) inhibitors, and will test the hypothesis that combinations of these agents with immunotherapies will be effective therapeutic strategies for BRCA-mutated and sporadic TNBC. Our preliminary data in preclinical models indicate that PARP inhibition can activate the STING pathway, alter tryptophan metabolism and stimulate the infiltration and activation of cytotoxic T cells, and that BBD inhibitors synergize with paclitaxel and PD-L1 blockade.
In Aim 1, the effects of PARP inhibition alone and in combination with PD-1 blockade on the immune microenvironment and on tumor growth will be assessed in an animal model of BRCA- associated TNBC and in clinical trials. Experiments will be conducted in mice, and will translate to a phase 2 trial in the neoadjuvant setting using niraparib or combined niraparib/PD-1 therapy, where changes in T cell infiltrate and pathologic complete response (pCR) rate will be defined. Preclinically, combined PARP inhibition and immune checkpoint blockade will be investigated in BRCA wild-type syngeneic TNBC models. We will also leverage a trial of talazoparib and avelumab in metastatic BRCA-associated and sporadic TNBC (TALAVE) in which biopsies obtained pre-treatment, after talazoparib alone and after the combination will be comprehensively evaluated for effects on the immune microenvironment.
In Aim 2, the effects of BBD inhibition alone and in combination with PD-L1 blockade and paxlitaxel will be evaluated in mouse models of TNBC as well as in a clinical trial. Changes in the composition and activation of components of the immune microenvironment will be assessed following BBD inhibitor (e.g., JQ1 and ZEN-3694) and PD-1/L1 treatment, with or without paclitaxel. A Phase 1 dose-escalation trial combining the BBD inhibitor ZEN-3694 with pembrolizumab and nab-paclitaxel will be performed, in which tumor biopsies will be studied to document changes in the immune microenvironment and in copy number and expression of CD274, encoding PD-L1. This project will improve our understanding of immune effects of targeted therapies and may identify biomarkers to aid the selection of patients most likely to benefit.
Administrative Core
Core Directors:
Kornelia Polyak, MD, PhD
Nancy U. Lin, MD
Geoffrey Shapiro, MD, PhD
The Administrative Core (Core A) will coordinate and integrate the multiple components of the Dana-Farber/Harvard Cancer Center (DF/HCC) Breast Cancer SPORE and provide scientific, administrative and fiscal oversight of the SPORE Projects, Cores, the Developmental Research Program (DRP) and the Career Enhancement Program (CEP). The Core directs the following activities:
- Administrative Management: provides the infrastructure for fiscal and administrative oversight
- Clinical Research Management: supports Breast SPORE investigators in conducting clinical trials and facilitates collaborations within the DF/HCC Breast Program and external sites.
- Integration of the SPORE within DF/HCC: promotes coordination and communication between SPORE investigators, the DF/HCC Breast Program and its established committees, as well as the DF/HCC community and its leadership.
- Patient Advocacy: integrates the Patient Advocacy Committee into the planning and evaluation of the Breast SPORE, with guidance from Lead Advocate Christine McLaughlin. The Core seeks to fully engage the patient advocates in the four Projects, the DRP, the CEP and Cores to ensure that the patient perspective is fully considered in SPORE-related research.
- Planning and Evaluation: provides scientific leadership and oversight for the SPORE Projects, the Cores, the DRP and the CEP. The Core also organizes meetings of the Breast SPORE External Advisory Board (EAB) and Internal Advisory Board (IAB).
Biostatistics and Computational Biology Core
Core Directors:
Meredith Regan, ScD
Nabihah Tayob, PhD
The Dana-Farber/Harvard Cancer Center (DF/HCC) SPORE in Breast Cancer Biostatistics and Computational Biology Core (Core B) collaborates and provides consultation on all research activities within the SPORE, including SPORE Projects, Developmental Research Program and Career Enhancement Program projects to ensure the highest standards of scientific rigor in areas of study design, data management and integrity, and data analysis and interpretation. The overarching goal is to promote translational research derived from fundamental discoveries in the laboratory that can lead to tangible clinical benefit.
The organization of biostatistical and computational biology expertise as a shared resource core is a cost-effective approach to ensure that collaboration is readily available to SPORE investigators and is an effective strategy to guarantee a high degree of integration among projects, which have interrelated analytic goals and needs. Core B has a wealth of experienced biostatisticians and computational biologists equipped with excellent computational support, including major commercial and public-use statistical software, and a large library of locally written software for design and analysis.
Biospecimen and Pathology Core
Core Director:
Deborah Dillon, MD
The Biospecimen and Pathology Core (BCP) serves the SPORE projects by maintaining tissue/blood repositories, providing pathology services and by developing and performing cutting edge assays. Core C also houses the Immuno-Oncology Sub-Core.
The overarching goal of the BPC is to facilitate translational research involving the acquisition and use of biological samples within the SPORE. To accomplish this, the Core will continue to offer a range of services for SPORE investigators and others in the Dana-Farber/Harvard Cancer Center (DF/HCC) breast cancer research community. These include:
- maintaining a tissue and blood repository;
- collecting, storing, processing, and analyzing tissue and blood from participants on SPORE clinical trials; and
- providing readily accessible pathology and technical services, integrated with clinical data. In addition to standard pathology techniques, the BPC also offers access to state-of-the-art technologies, including cell-free DNA collection and analysis, multiplex immunofluorescence, automated imaging, and genomic analyses.
The BPC will centralize and prioritize access to biological samples for SPORE investigators, as well as support the larger DF/HCC breast cancer research community. Pathology support is available at all stages of the research process. Well established collection and distribution processes are currently in place with an extensive archive of formalin-fixed, paraffin-embedded tissue specimens. The Core has also led the molecular annotation of existing biospecimens, developed cell-free DNA methodologies and has enhanced immuno-oncology expertise and capabilities. The BPC has direct involvement in each of the SPORE projects, as well as DRP and CEP projects, overseeing the collection, storage, quality assessment, and processing of clinical trial biopsies and blood samples, and supporting preclinical objectives.
Developmental Research Program
Program Directors:
Nikhil Wagle, MD
Leif W. Ellisen, MD, PhD
The Developmental Research Program (DRP) funds small investigator-initiated projects, in order to advance high quality, novel, early-phase research, foster new ideas in breast cancer research and move research projects from a pilot stage to a level where external funding for more mature research is possible. Preference is given to early career investigators, specifically from underrepresented populations, as well as more established investigators who wish to change their research focus to breast cancer, to study novel concepts and/or to collaborate closely with an early career investigator.
Career Enhancement Program
Program Directors:
Judy Garber, MD, MPH
Sara Tolaney, MD, MPH
The Career Enhancement Program (CEP) supports early career investigators, who have research concepts focused on the biology, prevention, diagnosis, and treatment of breast cancer. The purpose of the CEP is to help develop the careers of junior investigators committed to breast cancer, with the goal that these funds will support the awardees’ efforts to become independent. Due to the need to identify and develop breast cancer investigators from underrepresented backgrounds, we have prioritized recruitment of minorities for our CEP awards.