Dana-Farber Cancer Institute
Principal Investigator(s)
Kornelia Polyak, M.D., Ph.D.
Researcher, Professor of Medicine
Dana-Farber Cancer Institute, Harvard Medical School
Co-Leader, Cancer Cell Biology Program
Dana-Farber Harvard Cancer Center
450 Brookline Ave, Dana 740C
Boston, MA 02115
617-632-2106
Leif Ellisen, M.D., Ph.D.
Program Director, Breast Medical Oncology
Professor of Medicine, Harvard Medical School
Clinical Director, Breast and Ovarian Cancer Genetics
55 Fruit St.
Boston, MA 02214
617-726-4315
Geoffrey Shapiro, M.D., Ph.D.
Researcher, Senior Vice President, Developmental Therapeutics
Clinical Director, Center for DNA Damage and Repair
Institute Physician
Professor of Medicine, Harvard Medical School
450 Brookline Avenue
Boston, MA 02215
617-632-4942
Nancy U. Lin, M.D.
Associate Chief, Division of Breast Oncology,
Susan F. Smith Center for Women’s Cancers
Director, Metastatic Breast Cancer Program
Director, Program for Patients with Breast Cancer Brain Metastases
Medical Director, Breast Oncology Translational Hub
Director, Breast Oncology Cohorts and Biorepository Program
Senior Physician
Professor of Medicine, Harvard Medical School
450 Brookline Avenue
Boston, MA 02115
617-632-2335
Overview
Harvard Cancer Consortium (HCC) Specialized Program of Research Excellence (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 and three cores which are built around extensive collaborative work involving laboratory and clinical investigators as well as patient advocates.
Project 1 addresses mechanisms of resistance to antibody-drug conjugates (ADCs). Strategies will focus on overcoming resistance in triple-negative breast cancer (TNBC) through mechanism-based combinations, including those targeting PARP1 and the proteasome. Preclinical modeling of ADCs with targeted agents will be translated into a clinical trial.
Project 2 focuses on breast cancer brain metastases (BCBM) and leverages our xenografts from resected human BCBM, GEM models, and BCBM trials. Clinical studies will define ADC activity in BCBM. Preclinical studies will investigate PTEN loss as a driver of BC cell seeding to the brain and its targeting with PI3Kβ inhibition.
Project 3 builds on preclinical work demonstrating that BET bromodomain (BBD) inhibition synergizes with chemo-immunotherapy in TNBC, enhancing immunomodulation and efficacy. A clinical trial combining BBD inhibition, nab-paclitaxel and pembrolizumab will be conducted in TNBC patients, while BBD inhibition will also be evaluated to reverse CDK4/6 inhibitor resistance in ER+ breast cancer.
Project 4 focuses on BRCA-associated breast cancer and the short PFS achieved with PARP inhibitors (PARPis) or anti-PD-(L)1 by targeting immunosuppressive macrophages in the TME with CSF-1R blockade. PARPi effects on the TME will be validated in trial biopsies from metastatic and neoadjuvant settings. Combined anti-CSF-1R and PARP inhibition will be evaluated in a Phase 1 trial and preclinically to reverse acquired PARPi resistance.
The Administrative Core leads efforts in planning and communication, ensuring that existing HCC structures support SPORE research efforts. The Biospecimen and Pathology Core provides project services, maintains tissue and blood repositories, and houses the Immuno-Oncology Sub Core. The Biostatistics and Computational Biology Core provides biostatistical expertise and manages genomic data. The Developmental Research and the Career Enhancement Programs identify novel translational approaches in translational research and support early career breast cancer investigators.
With our Projects, Cores and research environment, the HCC SPORE in Breast Cancer is poised to make substantial translational contributions.
Project 1: Overcoming ADC Resistance Through Mechanistic Combinations
Project Co-Leads:
- Leif Ellisen, MD, PhD (Basic Co-Leader)
- Steven Isakoff, MD, PhD (Clinical Co-Leader)
This SPORE project aims to find new treatments for metastatic triple-negative breast cancer (mTNBC) that are more effective and cause fewer side effects. Our team of HCC researchers have led the development of several antibody-drug conjugates (ADCs) for advanced breast cancer, including the drug sacituzumab govitecan (SG). These treatments have shown better response rates, longer progression-free survival, and longer overall survival compared to standard chemotherapy.
Cancer can be difficult to treat when it shows resistance to therapy, either by not responding to the treatment from the beginning (initial resistance) or by becoming less responsive over time (acquired resistance). Our clinical and translational research program focuses on finding treatment combinations with ADCs that can overcome both initial and acquired resistance to therapy. We recently completed a phase 1b/2 clinical trial of SG and the PARP inhibitor talazoparib for mTNBC. The drugs were given in a sequential dosing schedule, meaning one after the other, based on our hypothesis that this schedule might reduce side effects and improve effectiveness. While giving the drugs sequentially lowered the risk of severe bone marrow suppression, compared to giving the drugs at the same time, the sequential combination still caused significant blood-related (hematologic) side effects. In this project, our team will explore the best ways to use newer ADC/PARP inhibitor combinations and test new combination treatments with ADCs.
- In Aim 1 we will carry out pre-clinical studies leading to the design and launch of a phase 1b/2 clinical trial combining a TROP-2 targeted, TOP1 inhibitor-based ADC with a new PARP1-selective inhibitor, since PARP1 inhibition is known to have a hematopoietic stem/progenitor-(blood-related) sparing effect. We will also study how treatment response relates to biomarkers of DNA damage and repair by analyzing samples from the trial and other patients, comparing the ADC/PARP1i combination to ADC alone.
- In Aim 2, we will test a new combination of an ADC with a targeted therapy, identified through CRISPR screens, that may improve effectiveness by both impacting the repair of TOP1-related damage and increasing TROP2 expression.
Together, these studies will support innovative, mechanism-based clinical trials using ADC combination therapies for patients with mTNBC.
Project 2: Rational Approaches to Improve Treatment Outcomes of Patients with Breast Cancer Brain Metastases
Project Co-Leads:
- Nancy Lin, MD (DFCI) (Clinical Co-Leader)
- Jean Zhao, PhD (DFCI) (Basic Co-Leader)
Brain metastases occur when cancer spreads to the brain, a serious and often life-threatening development for people with advanced cancer. These tumors are especially challenging to treat because many therapies can't reach the brain due to the protective blood-brain barrier (BBB). However, when cancer spreads, this barrier can become disrupted, creating what's called a blood-tumor barrier (BTB). Brain metastases are a devastating complication, and treatment options remain limited.
Recently, antibody-drug conjugates (ADCs), a type of targeted cancer therapy, have significantly improved outcomes for patients with metastatic breast cancer. However, most ADC trials have excluded patients with active brain metastases. Encouragingly, both laboratory and early clinical studies suggest that ADCs may be effective in treating brain metastases, likely because they can cross the BTB and reach the tumor.
Our research team recently discovered that blocking a protein called PI3Kβ can boost the immune system’s ability to fight tumors that are missing another protein called PTEN. Since PTEN loss is common in BCBM, we aim to explore whether combining PI3Kβ inhibitors with immunotherapy can help overcome immune resistance in these tumors. To test this, we’ll use advanced research models, including patient-derived xenografts (PDXs) and genetically engineered mouse models (GEMMs), to develop and evaluate ADC-based combination therapies that could lead to better outcomes for patients with BCBM.
- Aim 1: Improve the effectiveness of the HER2-targeted therapy trastuzumab deruxtecan (T-DXd) in BCBM that are HER2-positive or HER2-low. We will test combination treatments, including adding PI3Kβ inhibitors to help the immune system fight the cancer. These strategies will be studied both in the lab and through clinical trials in patients.
- Aim 2: Study the TROP2-targeted ADC therapy, datopotamab deruxtecan (Dato-DXd), in triple-negative breast cancer brain metastases, especially in cases where PTEN is lost. We will test whether combining Dato-DXd with PI3Kβ inhibitors improves treatment response and will also begin translating these findings into clinical trials for patients.
Our overall goal is to develop and advance new ADC-based therapies that work in the brain, helping address a critical treatment gap for patients with BCBM.
Project 3: BET Bromodomain Inhibitor Combinations in Breast Cancer
Project Co-Leads
- Kornelia Polyak, MD, PhD (DFCI) (Basic Co-Leader)
- Ana Garrido-Castro, MD (DFCI) (Clinical Co-Leader)
- Sara Tolaney, MD, MPH (DFCI) (Clinical Co-Leader)
Current treatments for advanced breast cancer, such as immune checkpoint inhibitors (ICIs) for triple-negative breast cancer (TNBC) and CDK4/6 inhibitors for estrogen receptor-positive (ER+) breast cancer, have shown some success however many patients still don’t respond or eventually develop resistance to these treatments. This project explores whether a newer class of drugs, called BET bromodomain inhibitors (BBDIs), can improve outcomes when used in combination with existing therapies.
Our lab data show that BBDIs can make chemotherapy and CDK4/6 inhibitors work better, even in resistant tumors, and may also enhance the immune system’s ability to fight cancer. We plan to test these promising combinations in both lab models and clinical trials.
- Aim 1: Test whether combining a BBDI with paclitaxel (a chemotherapy drug) and anti-PD-1 (an immune therapy) improves treatment response in models of metastatic and drug-resistant TNBC. We will look at how the tumor environment changes, including the role of immune cells like B cells and signs of tumor cell aging (senescence). A Phase 1 trial will test this combination in patients, using tumor biopsies to look for immune activity and PD-L1 expression.
- Aim 2: Test the combination of a BBDI with CDK4/6 inhibitors in ER+ breast cancer models that have developed resistance. We’ll also study this in a rat model of ER+ tumors. A Phase 2 clinical trial will assess how well this combination works and how safe it is in patients with ER+/HER2- metastatic breast cancer that no longer responds to hormonal therapy or CDK4/6 inhibitors.
Our goal is to find better combination therapies for advanced breast cancer and identify biomarkers that can help match patients to the treatments most likely to work for them.
Project 4: Combined Targeting of DNA Repair and Macrophage-Mediated Immunosuppression in BRCA-Associated Breast Cancer
Project Co-Leads:
- Geoffrey Shapiro, MD, PhD (DFCI) (Clinical Co-Leader)
- Jennifer Guerriero, PhD (BWH) (Basic Co-Leader)
- Filipa Lynce, MD (DFCI) (Clinical Co-Leader)
PARP inhibitors are standard treatment for breast cancers with BRCA mutations. They work by targeting a specific DNA repair weakness in these tumors and can also help activate the immune system. However, studies show that adding immune checkpoint inhibitors (like PD-1/PD-L1 blockers) hasn’t made PARP inhibitors more effective.
Our recent research suggests that this may be because PARP inhibitors also attract immune-suppressing cells called tumor-associated macrophages (TAMs), especially those with a marker called CSF-1R. Blocking CSF-1R reduces these TAMs and makes PARP inhibitors work better, especially when CD8+ T-cells are active. This project will explore this new strategy.
- Aim 1: Study tumor samples from patients with BRCA-associated breast cancer who were treated in clinical trials with PARP inhibitors, alone or in combination with immune therapies. We will use RNA sequencing and advanced imaging (CyCIF) to examine immune cells in the tumor, especially T-cells and TAMs, to understand how they interact and change during treatment.
- Aim 2: Run a Phase 1 clinical trial combining the CSF-1R-blocking drug axatilimab with the PARP inhibitor olaparib in patients with BRCA-related metastatic breast cancer who have not yet received PARP inhibitors or responded well to them. Tumor biopsies will help determine whether the treatment depletes harmful TAMs and improves immune activity.
- Aim 3: Use lab models of BRCA1-deficient breast cancer that have become resistant to PARP inhibitors to test whether adding CSF-1R blockers can overcome resistance. Since resistant tumors often have more TAMs and immune checkpoint activity, we will also test combinations with immune therapies (anti-PD-1 and anti-TIM-3).
Our goal is to understand how the tumor immune environment changes during PARP inhibitor treatment and to develop more effective combination strategies, especially for patients whose tumors are resistant to current therapies.
Administrative Core
Core Directors:
The Administration, Advocacy, Planning, and Communication Core (Admin Core) coordinates and integrates all components of the HCC SPORE in Breast Cancer, providing scientific, administrative, and fiscal oversight. Key functions include:
- Aim 1: Administrative Management
This aim provides fiscal and administrative oversight for the HCC SPORE in Breast Cancer, facilitates interactions with the HCC Breast Cancer Program and the larger HCC community, and ensures compliance with NIH policies. - Aim 2: Clinical Research Management
The Core will support the conduct of clinical trials by promoting collaboration with the HCC Breast Cancer Program and enabling access to patients, clinical data, and biospecimens for translational research. - Aim 3: Integration of the SPORE within HCC
This aim focuses on coordinating shared resources, promoting communication, supporting clinical trial development and access to biospecimens, and disseminating research advances beyond HCC to foster collaboration. - Aim 4: Patient Advocacy
The Core will integrate patient advocates into SPORE activities, expand the role of advocacy, and provide mentorship and training for the next generation of patient advocates. - Aim 5: Planning and Evaluation
This aim evaluates the progress of SPORE components, brings in new research directions, retires nonproductive efforts, leverages findings to secure additional funding.
Biospecimen and Pathology Core A
Core Directors:
The Biospecimen and Pathology Core (BPC) supports breast cancer research in Harvard Cancer Consortium (HCC) SPORE in Breast by collecting, processing, storing, distributing and analyzing biological samples, such as blood and tissue, from patients who have taken part in research studies.
The BPC works with four major hospitals and additional research sites to carefully track every sample from the moment it’s collected to when it’s used in a study. The team partners with clinical trial leaders and research committees, such as the HCC Breast Clinical Data and Biospecimens Users Committee, to make sure the studies done using the collected samples are novel, scientifically sound and practical.
The BPC provides many laboratory services, including histology, dissection, immunohistochemistry, FISH, DNA/RNA extraction, library prep, tissue microarrays, digital scanning, flow cytometry, and extraction of circulating free DNA. The BPC helps create models that mimic patient tumors in the lab (like organoids and PDX models). It also has a specialized team, the Immuno-Oncology Sub Core, that focuses on understanding the immune system’s role in cancer.
Clinical and specimen data are housed in the Breast Oncology Data Warehouse and the team includes pathologists, data scientists, lab techs, and research staff, supporting over 35,000 consented patients to date.
Biostatistics and Computational Biology Core B
Core Directors:
The Harvard Cancer Consortium (HCC) Specialized Program of Research Excellence in Breast Cancer (HCC SPORE in Breast Cancer) Biostatistics and Computational Biology Core (Core B) supports all SPORE activities, including research projects and other cores. It ensures studies are scientifically sound by helping with study design, data management, and data analysis. Since the SPORE’s goal is to turn lab discoveries into clinical advances, Core B plays a key role in supporting this work.
Core B is made up of experienced biostatisticians and provides access to powerful computing tools, including commercial, public, and custom-built software. It also brings together expertise in computational biology and bioinformatics from both SPORE Projects and HCC, encouraging smooth collaboration and data sharing. This shared resource model helps provide high-quality, cost-effective support for research.
Having biostatistics and computational biology expertise organized as a shared core is an efficient way to make sure SPORE investigators have the support they need. The projects have interrelated analytic goals and needs and a Biostatistics and Computational Biology Core as a shared resource is an effective strategy to guarantee a high degree of integration among projects.
Developmental Research Program
Program Co-Directors:
The Harvard Cancer Consortium (HCC) Specialized Program of Research Excellence (SPORE) in Breast Cancer’s Developmental Research Program (DRP) supports innovative, investigator-initiated translational research projects across HCC institutions. Backed by federal, institutional, and philanthropic funding, the DRP has a strong track record of success, including high-impact publications, new grants, and clinical trials. Proposals are solicited broadly and selected through a rigorous peer-review process led by SPORE leadership, faculty, and patient advocates, based on criteria such as novelty, feasibility, and clinical relevance. Funded investigators are expected to engage actively with the SPORE, report progress, and utilize shared resources. The DRP aims to advance high-quality, high-risk, novel, early-stage research, to foster new ideas in the breast cancer research field, and to move research projects from a pilot stage to a level where external funding for more mature project is possible. A secondary goal of the DRP is to create opportunities for early-career faculty or established investigators working on other fields who are interested in transitioning into breast cancer research.
Career Enhancement Program
Program Co-Directors:
The Career Enhancement Program (CEP) supports early-career investigators focused on translational breast cancer research by providing funding, mentorship, and integration into the SPORE program. CEP helps grow the field’s talent pool and develop future research leaders. Projects may evolve into full SPORE Projects within the Harvard Cancer Consortium (HCC) SPORE in Breast Cancer. CEP uses a transparent, peer-reviewed selection process, evaluating applicants based on leadership potential, scientific quality, and mentoring plans. The DRP/CEP Selection Committee, which includes SPORE investigators, HCC faculty, and patient advocates, makes funding recommendations. Broad calls for proposals to attract a competitive pool from across HCC and its affiliates, with a focus on supporting early-career investigators.
The CEP aims to:
1) Fund and mentor emerging translational researchers;
2) Build the next generation of leaders in breast cancer research;
3) Promote a strong mentoring culture; and
4) Generate preliminary data for future grants or SPORE projects.
CEP-supported research has led to high-impact publications, new grants, clinical trials, and career advancement.