Posted February 18, 2014
Panagiotis Konstantinopoulos, M.D., Ph.D., Dana-Farber Cancer Institute, Boston, Massachusetts
Ovarian tumors with BRCA1 or BRCA2 germline mutations are especially sensitive to platinum analogues and PARP inhibitors, resulting in increased survival rates for women with these tumors. It has been shown that certain sporadic, or non-genetic, tumors share this "BRCAness" phenotype. Prospective identification of sporadic tumors with the BRCAness phenotype is important to the appropriate clinical management of women bearing these tumors. Dr. Panagiotis Konstantinopoulos, a Fiscal Year 2009 Early Career Investigator in the Department of Defense (DoD) Ovarian Cancer Academy, developed a gene expression profile that can identify tumors with the BRCAness phenotype and demonstrated that these BRCA-like tumors are more sensitive to platinum and PARP inhibitors. Recently, he identified that expression of certain microRNAs, a class of gene expression regulators, was associated with enhanced sensitivity to platinum and PARP inhibitors and with improved survival outcomes in ovarian tumor samples. Dr. Konstantinopoulos hypothesizes that these microRNAs may downregulate genes involved in homologous recombination, an element of DNA repair that is often defective in cancer cells. His work on BRCAness and miRNAs aims to improve the understanding of responsiveness to chemotherapy in ovarian cancer, expand the cohort of patients who may benefit from novel agents such as PARP-inhibitors, and help detect BRCA-like ovarian tumors to facilitate a personalized treatment approach that may improve survival and quality of life for women with this disease.
The Connectivity Map is an online resource composed of a database of gene expression profiles from human cells that have been treated with various bioactive molecules and pattern-matching software that can be used to the query the database. Dr. Konstantinopoulos has applied the BRCAness gene expression signature to the Connectivity Map in an effort to identify candidate compounds that may be able to reverse resistance to PARP inhibitors. He found that two of the top-performing compounds were HSP90 inhibitors, suggesting a functional relationship between HSP90 inhibition and reversal of PARP inhibitor resistance. Dr. Konstantinopoulos demonstrated that a HSP90 inhibitor, at low, sublethal concentrations, increased sensitivity of ovarian cancer cells to a PARP inhibitor. Further treatment with the HSP90 inhibitor resulted in increased sensitivity of non-BRCA1/2 mutated ovarian cancer cells to olaparib and carboplatin. Dr. Konstantinopoulos hopes that this work will support future clinical trials of this combination treatment in ovarian cancer patients with resistance to PARP inhibitors.
Dr. Konstantinopoulos has made significant professional advancements since becoming a member of the DoD OCRP's Ovarian Cancer Academy in 2010. The Ovarian Cancer Academy is designed to function as an interactive virtual platform across institutional boundaries to provide mentoring, networking, peer support, and collaborative opportunities. The Academy aims to foster career investigators in ovarian cancer research whose dedication is critical to making significant strides toward the elimination of ovarian cancer. In 2011, Dr. Konstantinopoulos was promoted from Instructor to Assistant Professor at Beth Israel Deaconess Medical Center. In 2013, he transferred to Dana-Farber Cancer Institute where he is an attending oncologist in the Gynecologic Oncology Program and an Assistant Professor of Medicine at Harvard Medical School. He has served as an editorial board member for the Journal of Clinical Oncology and serves on the Experimental Medicine Committee of the Gynecologic Oncology Group. He is also a Principal or Co-Investigator for several clinical trials at Dana-Farber Cancer Institute.