DF/HCC Breast Cancer Specialized Program of Research Excellence (SPORE)

The Dana-Farber/Harvard Cancer Center (DF/HCC) SPORE in Breast Cancer seeks to improve the understanding and treatment of breast cancer using an innovative and highly translational approach. The program consists of four projects, three cores, a career enhancement program (CEP) and a development research program (DRP).

If you are interested in becoming involved in the Breast SPORE program, please contact Melissa Hughes, Melissa_hughes@dfci.harvard.edu.


PROJECT 1 — Overcoming Breast Cancer Resistance to CDK4/6 Inhibition

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 a clinical study in which paired biopsies are obtained prior to initiation of CDK4/6 inhibitors and when resistance develops. In triple-negative breast cancer, we will evaluate the possibility that lysosomal sequestration of CDK4/6 inhibitors limits their therapeutic efficacy. In preclinical work, we will determine if this sequestration can be reversed administering chloroquine and will also conduct a trial of palbociclib/chloroquine in RB-intact triple-negative disease.

  • Peter Sicinski, MD, PhD

    Dana-Farber Cancer Institute

  • Eric P. Winer, MD

    Yale Cancer Center

Inhibitors of cyclin-dependent kinases CDK4 and CDK6 have been approved for treatment of luminal-type estrogen receptor (ER)-positive breast cancers. Unfortunately, a large proportion of patients with breast cancer develops resistance to CDK4/6 inhibition.

In Aim 1, we will test our hypothesis that CDK4/6 resistant breast cancer cells become dependent on hyperactivation of the cyclin-dependent kinase CDK2 for proliferation. Consequently, we hypothesize that inhibition of CDK2 in CDK4/6 inhibitor-resistant cancer cells would block their proliferation. We further hypothesize that combined inhibition of CDK4/6 and CDK2 would have a synergistic effect and might prevent the development of resistant disease. Currently, a major limitation in studying the role of CDK2 is the absence of CDK2-specific inhibitors. To overcome this limitation, our laboratory has applied the ‘analog-sensitive’ kinase approach, which allows us to specifically, potently and reversibly inhibit CDK2 using a compound that does not inhibit any other kinases. In Aim 1, we will use the analog-sensitive approach to test the impact of CDK2 inhibition on proliferation of CDK4/6-inhibitor resistant tumors in vivo. We will also compare side-by-side the effects of potent CDK2 inhibition using our system, versus CDK2 inhibitors that are currently in clinical trials. In an effort to assess the role of CDK2 in the development of CDK4/6 resistance in the clinic, we will obtain 120 baseline biopsies from patients starting CDK4/6 inhibitor treatment to obtain 60 paired biopsies at baseline and when resistance develops. These biopsies will be interrogated for CDK2 activation status, and we will develop new approaches to gauge CDK2 activity in the clinical setting. 

In Aim 2, we will extend our investigations to triple negative breast cancer (TNBC). In contrast to luminal-type breast cancers, TNBC is intrinsically resistant to CDK4/6 inhibition. Nonetheless, we have observed that a significant fraction of human TNBC cell lines critically requires CDK4/6 for proliferation. Our preliminary data indicate that CDK4/6 inhibitors become sequestered into TNBC cell lysosomes, thereby blocking the inhibitors’ therapeutic effect. Importantly, we found that treatment of TNBC cells with compounds that inhibit lysosomal acidification, such as chloroquine, reverses the sequestration and renders TNBC cells sensitive to CDK4/6 inhibitor treatment. We also identified a new CDK4/6 inhibitor compound that on its own inhibits proliferation of TNBC cells. We will test the utility of combining CDK4/6 inhibitors with chloroquine for treatment of TNBC, using patient-derived xenografts, as well as short-term cultures of cells isolated directly from human tumors. We will also use these systems to evaluate the efficacy of the novel CDK4/6 inhibitor described above. We will conduct a phase I/II study of palbociclib and chloroquine to test the hypothesis that the addition of chloroquine can circumvent lysosomal sequestration, and patients in this trial will undergo paired biopsies to assess CDK4/6 inhibitor sequestration. The expected overall impact of this proposal is that it may provide a highly effective therapeutic strategy for overcoming acquired resistance to CDK4/6 inhibitors and may extend the benefits of anti-CDK4/6 therapy to patients with TNBC.


PROJECT 2 — Combination immunotherapy approaches to overcome therapeutic resistance in HER2-positive breast cancer

Project 2 uses two “co-clinical” trials – running randomized human trials and mouse experiments largely in parallel – to study two novel therapeutic approaches to enhance the antitumor immune response against HER2-positive breast cancers (CDK4/6 inhibition and dual PDL1 and 4-1BB targeting). Both approaches are based on preclinical data and will include local and international collaborators.

  •  Ian E. Krop, MD, PhD

    Yale Cancer Center

  • Shom Goel, MD, PhD

    Peter MacCallum Cancer Centre

Despite significant advances in the management of metastatic HER2+ breast cancer (BC), it remains incurable. The reason for this is that cancers invariably develop resistance to standard therapies – both cytotoxic chemotherapies and those that specifically target HER2. Modern attempts to improve upon standard therapies have largely focused on agents that inhibit HER2 downstream signaling more potently, but these have yielded only incremental benefits. Therefore, new treatment approaches are urgently needed. Recently it has become clear that HER2+ BCs are 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 therefore study two novel therapeutic approaches designed to boost the anti-tumor immune response against HER2+ BC further: 

  1. the use of CDK4/6 inhibitors, given together with trastuzumab and PD-1 blockade
  2. the addition of PDL1blockade and a 4-1BB agonist to chemotherapy and trastuzumab.

Both regimens are rationally designed, based on our convincing preclinical data showing that these approaches 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. Each Aim will also employ a “co-clinical trial” model, with mouse studies running in parallel to human trials. The animal experiments will be performed using our state-of-the-art transgenic model of human HER2- driven mammary carcinoma (MMTV-rtTA/tetO-HER2). Our mouse studies incorporate cutting edge technologies to understand the mechanisms of activity for these novel immunotherapy approaches, as well as detailed studies of resistance mechanisms (including next-generation sequencing and multiplexed immunofluorescent profiling of tumor tissue). Meanwhile, the trials involve serial collection of tumor biopsies and blood samples. Biospecimens from mice and patients will be analyzed in parallel, with each informing the other. Ultimately, these studies will:

  1. characterize the immune landscape of advanced HER2-positive BC in unprecedented detail
  2. determine whether either of the two novel approaches is an effective clinical strategy
  3. establish cellular mechanisms of activity for each regimen
  4. explore mechanisms of therapeutic resistance

This work has the potential to uncover new therapies that enhance immune responses against HER2-positive BC, and thus significantly improve patient outcomes.


PROJECT 3 — Improving therapeutic approaches for breast cancer brain metastases

Project 3 tackles the challenge of breast cancer brain metastases. Leveraging our unique collection of xenografts derived from resected human brain metastases, and our experience conducting brain metastasis-specific trials, we will test the biologic and clinical impact of two novel systemic therapy regimens.

Breast cancer brain metastases (BCBM) affect up to half of patients with advanced HER2+ breast cancer and 10-15% of patients with advanced ER+/HER2- breast cancer. Standard of care includes surgery and/or radiotherapy; however, these approaches can be associated with substantial toxicities, do not address systemic disease, and leave patients at risk for future central nervous system progression (CNS) and death. Despite their clinical impact, existing preclinical models of BCBM have been limited, and the factors which 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 major, persistent, and unmet medical need. Preclinical investigations, including our own, have suggested a role for at least two key pathways—PI3K/PTEN/mTOR and cyclin D1/CDK4—in the growth and maintenance of BCBM. 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 the 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), married with state-of-the art molecular pathology techniques.

In Aim 1, we will:

  1. test whether PTEN loss promotes the growth and maintenance of BCBMs, and evaluate the effects of genetic or pharmacologic restoration of PTEN expression
  2. evaluate brain-penetrant PI3K/mTOR inhibitors in preclinical models of BCBM and uncover potential mechanisms of site-specific resistance
  3. test the efficacy of combined PI3K/mTOR blockade in patients with HER2+ BCBM.

In Aim 2, we will: 

  1. evaluate the efficacy of CDK4/6 inhibition, alone and in rational combinations
  2. evaluate the efficacy and immuno-modulatory effects of CDK4/6 inhibitors, alone and in combination with immune checkpoint blockade and in varying genetic backgrounds
  3. 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 4 is focused on triple-negative breast cancer. We will perform comprehensive preclinical studies and clinical trials to determine whether targeted therapies can sensitize triple-negative tumors to immunotherapy. We will evaluate combinations of either PARP inhibitors or BET bromodomain inhibitors with immune checkpoint blockade.

Although several lines of evidence support the use of immunotherapy in triple-negative breast cancer (TNBC), the modest clinical efficacy achieved in current clinical trials suggests that the immunosuppressive microenvironment cannot be overcome by PD-1/PD-L1 blockade alone. In order to improve outcomes, this project will investigate the immunologic effects of two emerging 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. The rationale for this work is based on our preliminary data indicating 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 preclinical models.

Two specific aims are proposed. In Aim 1, the effects of PARP inhibition alone and in combination with PD-1blockade on the immune microenvironment and on tumor growth will be assessed in an animal model of BRCA associated TNBC and in a clinical trial. Experiments will be conducted in mice bearing TNBCs derived from the K14Cre;BRCA1f/f;p53f/f genetically-engineered mouse model, and will translate to a phase 2 trial in the neoadjuvant setting using niraparib or combined niraparib/PD-1 therapy, in which changes in T cell infiltrate and pathologic complete response (pCR) rate will be defined. Preclinically, combined PARP inhibition and PD-1 blockade will also be investigated in BRCA wild-type syngeneic TNBC models, including EMT-6 and JC.

In Aim 2, the effects of the BBD inhibitor JQ1 alone and in combination with PD-L1 blockade will be evaluated in the same syngeneic and genetically-engineered mouse models of TNBC used in Aim 1, as well as in a clinical trial. Changes in the composition and activation of components of the immune microenvironment will be assessed following JQ1 or JQ1 and PD-L1 treatment, with or without paclitaxel. Finally, a Phase 1 dose-escalation trial combining the JQ1 derivative RO6870810 and atezolizumab as a doublet, or with paclitaxel as a triplet, will be performed using concomitant and sequential schedules, 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. The successful completion of this project will improve our understanding of the immune effects of these targeted therapies and may identify biomarkers to aid the selection of patients most likely to benefit.


Patient Advisory Committee

The Breast Cancer Advocacy Group (BCAG) is a group of breast cancer advocates that focuses on influencing breast cancer research to reflect patient concerns by collaborating with DF/HCC researchers in the development and oversight of research to improve patient outcomes under the leadership of Elizabeth Frank, EdM. 

Advocates come from diverse backgrounds but share their interest in science, the research process, and desire to improve outcomes for future patients. Most of the advocates are breast cancer survivors or are living with breast cancer. Advocates come from both science and non-science backgrounds, are both retired and working and have a varied level of experience with research. Many of the advocates have attended one or more of NBCC’s Project LEAD courses. In addition to their activities with the BCAG, advocates are affiliated with different breast cancer organizations including Susan G. Komen for the Cure, Living Beyond Breast Cancer, the National Breast Cancer Coalition, Stand Up to Cancer, The Metastatic Breast Cancer Network and The Translational Breast Cancer Research Consortium.

BCAG members provide an informed patient perspective to DF/HCC investigators involved in all areas of translational and clinical research. In the Breast SPORE, each project has an advocate team consisting of 3 advocates who attend meetings, weigh in on decisions, and provide a patient perspective their respective projects.  In addition, the group focuses on topics directly affecting the patient experience, such as tissue banking, consenting for clinical trials, and the sharing of research results with patient participants. The group has substantial experience in partnering with clinicians and researchers to generate ideas for new directions in research and has co-developed and jointly led projects. 

The BCAG members participate in a spectrum of research activities including:

  • Membership on the DF/HCC Breast SPORE Project teams and Committees
  • Working sessions with investigators to develop new research ideas for grant funding
  • Reviewing new concepts for clinical trials within the DF/HCC Clinical Trials Core
  • Reviewing informed consent documents and protocols for clinical trials
  • Reviewing grants for DF/HCC Women’s Cancer Center and SPORE funded Awards
  • Participating in ongoing research projects funded by the National Cancer Institute (NCI), The Agency for Health Research and Quality (AHRQ), Susan G. Komen for the Cure, the Department of Defense Breast  Cancer Research Program (DoD BCRP) and the Patient Centered Outcomes Research Institute (PCORI)

To keep our knowledge as current as possible, BCAG members pursue local and national educational opportunities. We meet monthly or more as needed and often invite local investigators to present their research for discussion. Advocates have a standing invitation to DF/HCC Breast and GYN Cancer Center educational seminars and research programs and to the annual Harvard Medical School Continuing Education Course in Breast Oncology. In addition, advocates are encouraged to attend national programs for advocates such as the NBCC.  



The Administrative Core is the epicenter of scientific, fiscal and administrative oversight. It will lead efforts in planning and communication, and also houses the Patient Advocacy Committee. Core A will ensure that existing DF/HCC structures support the SPORE clinical research efforts.

The role of the Administration, Advocacy, Planning and Communication Core (Administrative Core - Core A) is to coordinate and integrate the multiple components of the Dana-Farber/Harvard Cancer Center (DF/HCC) Breast Cancer SPORE and to provide scientific, administrative and fiscal oversight of the SPORE Projects, Cores, the Developmental Research Program (DRP) and the Career Enhancement Program (CEP).
  • Administrative Management: Core A will facilitate the coordination of the Breast SPORE within the DF/HCC to meet our scientific aims. Core A will provide the infrastructure for fiscal and administrative oversight for the Breast Cancer SPORE, including financial accounting and reporting, coordination of research agreements and pre-and post-award monitoring and reporting in close collaboration with the grants management office at Dana-Farber Cancer Institute.
  • Clinical Research Management: Core A will support all investigators in the Breast SPORE conducting clinical trials and facilitate the interaction and collaborations in the preparation, review and activation of clinical studies within the DF/HCC Breast Program and external sites. 
  • Integration of SPORE within DF/HCC: Core A will promote coordination and communication between SPORE investigators, the DF/HCC and its leadership, the DF/HCC Breast Program and its established committees that support clinical trial development, review, activation and management, as well as access and use of biospecimens and associated clinical data. Core A will coordinate the Shared Resources Leadership Committee comprised of the core directors, project leaders, patient advocates and DF/HCC investigators, as well as monthly Research-in-Progress meetings for frequent updates on progress in the Breast SPORE.
  • Patient Advocacy: The Core will integrate the work of our large and highly interactive Breast Cancer Advocacy Group into the planning and evaluation of the Breast SPORE, with guidance from Elizabeth Frank, EdM, as co-investigator of Core A. The Core will seek to fully engage the patient advocates in the four SPORE Projects, the DRP, the CEP and the Cores to ensure that the patient perspective is taken into account in the clinical/translational research. 
  • Planning and Evaluation: Core A will provide rigorous scientific leadership and oversight for the SPORE Projects, the Cores, the DRP and the CEP. Core A will organize meetings of the Breast SPORE External Advisory Board (EAB) and Internal Advisory Board (IAB) for evaluation on findings and progress across the Breast SPORE.

SPORE Administrators:
Melissa Hughes, Associate Director, melissa_hughes@dfci.harvard.edu  | 617-632-2268
Claudia Cassano, Administrative Assistant, claudia_cassano@dfci.harvard.edu  | 617-632-6876
Samuel Keller, Grants Administrator, samuel_keller@dfci.harvard.edu  | 617-632-4336



The Biostatistics and Computational Biology Core provides specialized expertise in biostatistics and management of genomic data.

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 specific aims of Core B 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 Enhancement projects, and other SPORE Cores
  2. provide consultation on all issues of data management and integrity, including: a) data collection and storage, b) data transfer and quality assurance, c) statistical and computational biology software and programs, and d) integration of preclinical data and correlative findings with parameters and outcomes from clinical studies databases
  3. provide short-term biostatistics and computational biology consulting to the entire group of SPORE researchers.

Organizing 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.



The Biospecimen and Pathology Core will maintain tissue/blood repositories for the SPORE projects and for investigators outside of the SPORE. It also provides critical pathology services for the projects and will perform cutting edge assays. Core C also houses the Immuno-Oncology Sub Core. The DRP and CEP identify novel approaches to translational questions in breast cancer and support young investigators.

The overarching goal of the Biospecimen/Pathology Core (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:

  1. providing a tissue and blood repository
  2. collecting, storing, processing and analyzing tissue and blood from participants on SPORE clinical trials
  3. 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. Fresh tissue collection follows well-established protocols that are currently in place at three hospitals (Brigham and Women's Hospital [BWH], BW Faulkner Hospital [BWFH], and Massachusetts General Hospital [MGH]).

Fixed tissue specimens are collected at all four hospitals (BWH, BWFH, MGH, and Beth Israel Deaconess Medical Center [BIDMC]). Blood collections take place at all outpatient locations. Specimen locations and linked clinical and pathologic annotations are maintained and distributions are tracked in caTissue. Requests for biospecimen use are reviewed and approved by a multidisciplinary DF/HCC Breast Data and Specimen Users Committee with representation across participating institutions. Pathology support is available at all stages of the research process. We will also maintain the same strong collection and distribution processes currently in place with added focus on collecting triple-negative breast cancer specimens, enhancing the formalin-fixed, paraffin-embedded (FFPE) research tissue archives, adding cell-free DNA methodologies, improving the molecular annotation of existing biospecimens and enhancing immuno-oncology expertise and capabilities. The BPC will have direct involvement in each of the proposed SPORE projects, overseeing the collection, storage, quality assessment and processing of clinical trial biopsies and blood samples, and supporting preclinical objectives. The Core will also work with investigators throughout the DF/HCC and the wider breast research communities, including projects supported through career development program awards and developmental projects.


Career Enhancement Program

The Career Enhancement Program (CEP) will support early career breast cancer researchers, 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 young investigators committed to breast cancer, and our goal is that these funds will support the awardees’ efforts to become independent researchers. The CEP is focused on young investigators at a junior faculty level. More senior individuals who wish to change their research focus to breast cancer are encouraged to apply for the SPORE Developmental Research Program awards, not the CEP, unless they are eligible for the Special Minority Career Advancement Award. Because of the need to identify and develop breast cancer researchers from underrepresented backgrounds, we have prioritized recruitment of minorities to our CEP awards and have also created a special award exclusively for underrepresented minority candidates.

*Click the Read More button below to see publications


*Coming Soon



Developmental Research Program

The Developmental Research Program (DRP) will fund small investigator-initiated projects with direct cost budgets of between $50,000-75,000. In the previous Dana-Farber/Harvard Cancer Center (DF/HCC) Breast SPORE, DRPs led to publications, grants, and clinical trials. One of the DRP awards from the previous SPORE has established the basis of a large portion of Project 3 of this grant, and others have formed the projects in the current proposal or have been incorporated into one of the Projects.

The process for soliciting applications, awarding grants, monitoring research progress, and making decisions about ongoing funding are described in this section. The DRP has a transparent peer-reviewed selection process that incorporates defined criteria for funding decisions. The committee that oversees the process and selects the award recipients is the Developmental Research Program and Career Enhancement Program Awards (DRP/CEP) Review Committee. The DRP will initiate a broad call for proposals to ensure the most promising early-phase research projects receive meritorious funding, and investigators at all DF/HCC member institutions will be eligible to submit proposals.

The DF/HCC has a large and talented investigator group to provide a wealth of applications from which to choose, and we anticipate a robust response to each request for applications that is announced.

*Click the Read More button below to see publications


*Coming Soon