October 01, 2024 – Announcements
Newly released: DF/HCC Breast Cancer Program Retreat Recording
CO-LEADER
CO-LEADER
CO-LEADER
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 Kate Bak, kate_bak at dfci.harvard.edu.
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.
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 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.
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:
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:
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 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:
In Aim 2, we will:
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 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.
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 Paula Steeves and Susan Koegel, PhD.
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:
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.
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:
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:
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.
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.
Jan Heng, PhD | Beth Israel Deaconess Medical Center | Molecular Impact of Transgender Testosterone Therapy in the Breast |
Laura Spring, MD | Massachusetts General Hospital | Leveraging the neoadjuvant setting as a translational model for drug development in TNBC |
Jaymin Patel, MD | Beth Israel Deaconess Medical Center | Identifying drivers of disease recurrence in HR+ breast cancer |
Seth Wander, MD | Massachusetts General Hospital | Genomic and Molecular Predictors of Response to Abemaciclib after Progression on a CDK4/6 |
Ada Waks, MD | Dana-Farber Cancer Center | Integrative computational biology of large scale molecular datasets to tackle immunotherapy resistance in breast cancer |
Evanna Mills, PhD | Harvard Medical School | Metabolic rewiring of tumor associated macrophages for the treatment of breast cancer |
Needa Brown, PhD | Northeastern University | STING agonist drug delivery formulations synergize with PARPi to treat resistant, metastatic advanced breast cancer |
*Bolded names are CEP recipients
**Underlined names are DF/HCC SPORE in Breast Cancer Collaborators
Baker GM, Guzman-Arocho YD**, Bret-Mounet VC, Torous VF, Schnitt SJ, Tobias AM, Bartlett RA, Fein-Zachary VJ, Collins LC, Wulf GM and Heng YJ. Testosterone therapy and breast histopathological features in transgender individuals. (2021) Mod Path, 34, 85-94.
Baker GM, Bret-Mounet VC, Xu J, Fein-Zachary VJ, Tobias AM, Bartlett RA, Clohessy JG, Vlachos IS, Massicott ES, Wulf GM, Schnitt SJ and Heng YJ. Toker cell hyperplasia in the nipple-areolar complex of transmasculine individuals. (2023) Mod Pathol, 36, 100121.
Heng YJ, Zhang KJ, Valero MG, Baker GM, Fein-Zachary VJ, Irwig MS and Wulf GM. Invasive ductal carcinoma of the breast in a transgender man: a case report. (2023). Case Rep Oncol. In Press.
Heng YJ, Baker GM, Fein-Zachary VJ, Guzman-Arocho Y, Bret-Mounet VC, Massicott ES, Gitin S, Russo P, Tobias AM, Bartlett RA, Varma G, Kontos D, Yaghjyan L, Irwig MS, Potter J, and Wulf GM. Effect of testosterone therapy on breast tissue composition and density in trans masculine individuals. Under Review at JAMA Open.
ASCO Abstract: Laura Spring, Sara M. Tolaney, Neelam Vijay Desai, Geoffrey Fell, Lorenzo Trippa, Amy H. Comander, Therese Marie Mulvey, Shannon McLaughlin, Phoebe Ryan, Aron S. Rosenstock, Ana Christina Garrido-Castro, Filipa Lynce, Beverly Moy, Steven J. Isakoff, Nadine M. Tung, Elizabeth A. Mittendorf, Leif W. Ellisen, and Aditya Bardia. Phase 2 study of response-guided neoadjuvant sacituzumab govitecan (IMMU-132) in patients with localized triple-negative breast cancer: Results from the NeoSTAR trial. Journal of Clinical Oncology 2022 40:16_suppl, 512-512.
AACR Abstract: AACR Special Conference on Advances in Breast Cancer Abstract (Platform presentation to be delivered 10/2023) Laura M. Spring, Bogang Wu, Ting Liu, Jacob Geisberg, Simona Cristea, Veerle Bossuyt, Rachel Occhiogrosso Abelman, Nicole Peiris, James Coates, Siang-Boon Koh, Mengran Zhang, Lianne Ryan, Beverly Moy, Steven J. Isakoff, Sara M. Tolaney, Franziska Michor, Aditya Bardia, and Leif W. Ellisen. Intratumoral heterogeneity drives resistance to Antibody Drug Conjugate therapy: Analysis of the NeoSTAR trial of neoadjuvant Sacituzumab govitecan for localized TNBC.
Brett JO, Dubash TD, Johnson GN, Niemierko A, Mariotti V, Kim LSL, Xi J, Pandey A, Dunne S, Nasrazadani A, Lloyd MR, Kambadakone A, Spring LM, Micalizzi DS, Onozato ML, Che D, Nayar U, Brufsky A, Kalinsky K, Ma CX, O'Shaughnessy J, Han HS, Iafrate AJ, Ryan LY, Juric D, Moy B,Ellisen LW, Maheswaran S, Wagle N, Haber DA, Bardia A, Wander SA. A Gene Panel Associated With Abemaciclib Utility in ESR1-Mutated Breast Cancer After Prior Cyclin-Dependent Kinase 4/6-Inhibitor Progression. JCO Precis Oncol. 2023 May;7:e2200532. doi: 10.1200/PO.22.00532.
October 01, 2024 – Announcements
Newly released: DF/HCC Breast Cancer Program Retreat Recording
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.
Jennifer Ligibel, MD (DFCI) | Pilot study of the impact of a physical activity intervention on proliferation and immune markers in normal breast tissue in women with high mammographic breast density |
Geoffrey Shapiro, MD, PhD (DFCI) | Modulation of the cGAS/STING pathway to augment PARP inhibitor efficacy and reverse resistance in triple negative breast cancer |
Sara Tolaney, MD (DFCI) | Immune effects of sacituzumab govitecan combined with pembroluzimab in PDL1 negative metastatic triple negative breast cancer |
Aditya Bardia, MD, PhD (MGH) | Targeting DNA damage and repair pathways with sequential therapy in metastatic triple negative breast cancer: Focus on biomarkers |
Elizabeth Mittendorf, MD, PhD and Sandra McAllister, PhD (BWH) | Immunologic Weathering: A novel mechanism of poor outcomes in non-hispanic Black breast cancer patients |
Shailja Pathania, PhD (UMass) | BRCA1 heterozygosity driven breast cancer mouse model to design new preventative strategies |
Dominik Glodzik, PhD (HMS) | Sensitive detection of mutational signatures for early detection of breast cancer in patients with germline BRCA1/2 mutations |
Pantelidou C, Jadhav H, Kothari A, Liu R, Wulf GM , Guerriero J L, Shapiro GI. STING agonism enhances anti-tumor immune responses and therapeutic efficacy of PARP inhibition in BRCA-associated breast cancer. Npj Breast Cancer. 2022 Sep 6;8(1):102. doi: 10.1038/s41523 – 022 - 00471- 5
October 01, 2024 – Announcements
Newly released: DF/HCC Breast Cancer Program Retreat Recording