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New awards promote collaboration in women’s cancers research

Joan Brugge, PhD (HMS)

Dana-Farber/Harvard Cancer Center has announced its first round of funding through the Men’s Collaborative to Cure Women’s Cancers, an unprecedented partnership providing a vehicle for men to support cutting edge research in breast and gynecologic cancers across the DF/HCC community.

Awards support investigators conducting innovative translational research in women’s cancers spanning the disciplines of basic biology, population studies, outcomes, or social science. The emphasis is on translational research. Special consideration was given to studies focused on prevention and treatment with a high probability of near-term patient benefit and impact on future research and treatment. Five awards were made to outstanding applicant teams.

Congratulations to the first round of funding recipients:

Evaluating ATAD2 as a therapeutic target in MYC-driven breast, endometrial, and ovarian cancers
PI: Rameen Beroukhim, MD, PhD (DFCI)
Co-PI: James Bradner, MD (DFCI)

The oncogene MYC has long been known to be a major driver of cancer development and a potential therapeutic target. ATAD2, a gene that neighbors MYC and is almost always co-amplified with it, appears to promote MYC activity and is necessary for the survival of MYC-dependent cancers. The ATAD2 gene encodes a bromodomain-containing protein, and we have recently developed specific inhibitors to bromodomain-containing proteins such as the related protein BRD4. The goal for this project will be to develop a specific inhibitor of ATAD2 and identify genetic and molecular features that mark breast, ovarian, and endometrial cancers that are likely to be sensitive to its use. These experiments will serve as the basis for developing ATAD2 as a therapeutic target in MYC-driven women’s cancers and for identifying patients who are most likely to benefit from its use. 

Combination of PI3K inhibitors with inhibitors of DNA damage repair to treat breast cancer
PIs: Gerburg Wulf, MD, PhD (BIDMC), Lewis Cantley, PhD (BIDMC), Ursula Matulonis, MD (DFCI), Eric Winer, MD (DFCI)

Metastatic, hormone-refractory breast cancer remains an incurable illness. Currently used chemotherapy regimen will delay, but not cure metastatic disease. Newer agents that target the genetic mutations that tumor cells harbor have proven effective to delay the progression of the disease, but as single agents, have not proven curative. We have found the combination of a PARP-inhibitor with a PI3-kinase inhibitor delayed tumor progression in a mouse model of aggressive breast cancer, and in some instances even led to remission of the cancer. Based on these pre-clinical observations, we will conduct an early phase clinical trial entitled “Phase I study of the oral PI3-kinase inhibitor BKM120 and the oral PARP inhibitor olaparib in patients with recurrent triple negative breast cancer or high grade serous ovarian cancer.” We will study whether responsiveness to this combination is restricted to BRCA1-related breast cancers, and conduct correlative studies in biopsies from tumors of patients on this study to understand the mechanisms of action and resistance to this promising treatment combination, and to postentially identify biomarkers of response.

Identifying an miRNA signature for PARP-inhibitor and platinum-sensitivity in ovarian cancer
PI: Dipanjan Chowdhury, PhD (DFCI)
Co-PI: Joyce Liu, MD, MPH (DFCI)

PARP-inhibitors are a new therapy emerging in ovarian cancer that may be most effective in those tumors where the cancer cells cannot effectively repair their DNA due to decrease and/or loss of BRCA1 or BRCA2 or other players in DNA repair. It would be of significant clinical interest to be able to predict which patients will be able to respond to PARP-inhibitor therapy in order to better direct therapy based upon molecular understanding of their tumors; however, a clinical biomarker that can predict for such sensitivity has not yet been developed. Prior work by us has shown that certain miRNAs can decrease the expression of BRCA1 and affect the ability of cancer cells to efficiently repair DNA. This project will identify a miRNA signature associated with platinum- and PARP-inhibitor sensitivity as a potential biomarker in human ovarian cancer.

Accelerating the translation of PI3K-targeted therapy for HER2+ breast cancer brain metastases
PIs: Jean Zhao, PhD (DFCI), Keith Ligon, MD, PhD (DFCI), Nancy Lin, MD (DFCI)

Women diagnosed with advanced HER2+ of breast cancer face a 30-50% risk of brain metastasis with an 80% mortality rate. In a cruel irony, trastusumab, a therapy that targets the HER2 protein and significantly improves the outlook for HER2+ breast cancer patients actually increases the risk of brain metastasis because the therapeutic agent cannot cross the blood brain barrier (BBB), a protective division between blood and brain. The HER2+ tumor cells, however, can penetrate the BBB and expand in the brain. The HER2 molecule is critical for the uncontrolled growth of cancer cells and acts through the PI3K pathway. In preclinical studies, HER2+ breast tumor growth can be blocked by small molecule PI3K inhibitors. In fact, a PI3K inhibitor (BKM120) currently in clinical trial can cross the BBB. This project will test whether BKM120 can reach the HER2+ breast tumor cells and block their growth within the brain. The work will not only translate our basic research directly into clinical benefits for near-term patients but also have a significant impact on future treatment of and research on metastatic breast cancer.

Rational design of novel combination therapies for ovarian cancer
PIs: Joan Brugge, PhD (HMS), Ronny Drapkin, MD, PhD (DFCI), Ursula Matulonis, MD (DFCI)

This project focuses on targeting the PI3K/mTOR-pathway and the adaptive responses that induce drug resistance. The Brugge laboratory has identified mechanisms of resistance to drugs targeting this pathway, and developed drug combinations to abrogate drug resistance and to efficiently kill remaining drug resistant cancer cells. This resistance mechanism involves a drug-induced adaptive response that activates survival pathways in drug-treated cells, thus protecting cells from the cytotoxic effect of the inhibitors. This collaborative inter-institutional research project will evaluate the protective adaptive responses to drugs in clinical trials that target the PI3K/mTOR-pathways using primary human tumor cells obtained from ascites or pleural fluid, both in relapsed pre-treated patients and in treatment-naïve patients. We will design and test combination therapies to abrogate the drug-induced resistance based on the drug-induced program for each patient. These studies will provide clinically relevant information on the efficacy of the PI/3K/mTOR inhibitors for treatment of human tumors that inform clinical trials and provide the basis for a Multi-PI or SPORE project application.

About the Men’s Collaborative to Cure Women’s Cancers
The Dana-Farber/Harvard Cancer Center (DF/HCC) Men’s Collaborative to Cure Women’s Cancers is an initiative to support cutting-edge, collaborative research in breast and gynecologic cancers across the Harvard academic medical community. The mission of the Collaborative is to provide a vehicle for men to come together as a unified force to support women’s cancers research; maximize the impact of women’s cancers research by fostering Harvard-wide collaboration through DF/HCC; and grow the next generation of women’s cancers researchers by supporting the best Harvard faculty. For more information, visit http://www.womenscancersclassic.com/tmc-mission.html.

About Dana-Farber/Harvard Cancer Center
Dana-Farber/Harvard Cancer Center (DF/HCC) is the largest comprehensive cancer center in the country, bringing together the cancer research efforts of seven member institutions: Beth Israel Deaconess Medical Center, Brigham and Women's Hospital, Children's Hospital Boston, Dana-Farber Cancer Institute, Harvard Medical School, Harvard School of Public Health, and Massachusetts General Hospital.

Funded by a grant from the National Cancer Institute, DF/HCC consists of more than 1,000 researchers with a singular goal — to find new and innovative ways to combat cancer. For more information, visit www.dfhcc.harvard.edu.