Sidney Kimmel Cancer Center

Breast Cancer Program

The overarching mission of the Breast Cancer Program is to decrease the incidence and morbidity of breast cancer through discovery and translation into practice in the SKCC catchment area and beyond. This goal is accomplished by taking a multidisciplinary and collaborative approach to discover new aspects of breast cancer epidemiology and disparities, by designing novel interventions to take advantage of modifiable behaviors to decrease disease risk or morbidity, by developing novel imaging and therapeutic interventions, by elucidating new novel molecular mechanisms of disease and progression, and by catalyzing the translation of these findings into the clinic.

The Breast Cancer Program is comprised of new leadership and is led by Daniel Silver, MD PhD, Nicole Simone, MD, and Mauricio Reginato, PhD, (Drexel University, DU, Consortium Member). BC is composed of 26 basic, population, and clinical researchers. Members of the program have expertise in all aspects of breast cancer research, and participate in multiple collaborative grants and high impact publications.

Leadership

file

Program Leader- Daniel P. Silver MD PhD is a practicing medical oncologist in the SKCC breast oncology and genetics clinics, and runs a basic and translational laboratory focused on breast cancer. Prior to joining SKCC, he trained with Dr. David Baltimore at MIT, then finished training at the Dana-Farber Cancer Institute, where he worked with Dr. David Livingston on BRCA1/2 and DNA repair, and as a faculty member, on identifying new targets for therapy. He has extensive experience in basic and translational science, having participated in a clinical trial that altered thinking about the therapy of Triple Negative Breast Cancer (TNBC). He is the lead author on a widely-cited paper reporting a clinical trial which showed that cisplatinum has efficacy in sporadic TNBC (Silver et al., J Clin Oncol, 2010). Dr. Silver and his colleagues showed that the number of regions of telomeric allelic imbalance (NTAi) predicted the response of TNBC to platinum (Birkbak et al., Cancer Discovery,2012). His patent on this method has been licensed and is a core technology in Myriad’s Homologous Recombination Deficiency (HRD) assay, now the subject of a multi-institutional prospective trial (NCT01982448). His laboratory has recently uncovered a new oncogene, MECP2, which is amplified in 33% of TNBC and 38% of ovarian cancers, and may represent a new target of therapy in this disease as well as in other cancers (Neupane et al., Cancer Discov, 2016). He holds a DOD Breakthrough grant on MECP2. Dr. Silver has served on a number of grant review panels, including the DOD breast cancer study section and at the programmatic level, for the Komen Foundation. He holds three patents based on his laboratory work.

file

Co-Leader -  Nicole L. Simone MD is an Associate Professor of Radiation Oncology at SKCC, and Radiation Director for SKCC. She received her MD from Rutgers – New Jersey Medical School and did her radiation oncology training at the National Cancer Institute. She was promoted to the staff level at NCI, where she reported the long-term results of the NCI randomized breast conservation clinical trial and completed a study evaluating the long-term toxicity caused by cancer treatment. She then accepted a position at SKCC, where she was successfully recruited as a Co-Leader of the SKCC Breast Cancer Program. Dr. Simone’s laboratory has contributed significantly to studying regulation of microRNAs and the downstream effects of microRNAs on cell metabolism via dietary alterations. Her laboratory demonstrated for the first time that caloric restriction (CR) modifies microRNA expression (Ørom et al., Cell Cycle, 2012). The Simone laboratory then explored the physiologic impact of CR and demonstrated that CR can augment radiation therapy (Saleh et al., Cell Cycle, 2013), which she then translated directly into a clinical trial using diet during radiation for early stage breast cancer patients (NCT01819233). The lab found the same improved physiologic response of the primary tumor in vivo when CR was combined with chemotherapy, which was translated directly to a clinical trial (NCT02827370). Dr. Simone’s laboratory also investigated the role of microRNAs in the ability of CR to decrease metastatic disease burden via control of the ECM (Jin et al., Breast Cancer Res Treat, 2014; Simone et al., Cell Cycle, 2016) which is being considered as a NRG Oncology clinical trial concept. These findings led to her third IIT in which diet modulation prior to definitive oncologic surgery for patients with endometrial, prostate, and breast cancer will be evaluated to favorably alter expression of microRNAs as drivers of cancer progression (NCT02983279). On the national level, she has been appointed to committees within the American Society for Radiation Oncology (ASTRO), including the scientific council, and is a member of several NRG Oncology Committees including the Breast Committee, the Breast Translational Committee, the Cancer Prevention and Control Committee, and the Survivorship Committee. She mentors junior faculty for the Radiation Research Society. Dr. Simone sits on several study sections and has sat on a DoD Breast Cancer study section consecutively for the last 9 years.

file

Co-Leader - Mauricio J. Reginato, PhD pursued his PhD training at the University of Pennsylvania, in the lab of Dr. Mitchell Lazar, and then completed postdoctoral training at Harvard Medical School under Dr. Joan Brugge. In 2004 Dr. Reginato established a vigorous and well-funded research laboratory in the Department of Biochemistry and Molecular Biology at Drexel University (DU) College of Medicine, where he was promoted to Professor (with tenure). Dr. Reginato became a member of SKCC in 2012 and was subsequently appointed Co- Leader of BC after the SKCC leadership change. For the past 18 years, Dr. Reginato’s research focuses on understanding alterations in signaling pathways in breast cancer. His work has uncovered pathways regulating anoikis and resistance by HER2 in breast cancer cells using standard and three-dimensional epithelial culture assays. Dr. Reginato’s lab has shown that hypoxia, via HIF-1a, is a potent inhibitor of anoikis of mammary epithelial cells and causes disruption of epithelial ductal architecture in vitro (Whelan, et al., Mol Biol Cell, 2010). In addition, his lab showed that HER2-positive breast cancer cells require HIF-1a for oncogenesis in vivo, that HIF-1a contributes to anoikis-resistance of these cells in vitro (Whelan, et al., J. Biol Chem, 2013), and that hypoxia and HIF-1a can cause resistance to targeted therapy against HER2-positive breast cancers (Karakashev, et al., Oncotarget, 2015). Dr. Reginato’s lab was also the first to show that a nutrient-sensing pathway that regulates sugar-based protein modification, called O-GlcNAcylation, is highly elevated in breast and other cancers and is required for growth, invasion and metastasis in vivo (Caldwell, et al., Oncogene, 2010) and regulates cancer cell metabolism via regulation of HIF-1a (Ferrer, et al., Molecular Cell, 2014). He is currently testing novel inhibitors of this pathway using preclinical breast cancer models. His work has been funded by NIH, DOD, and PA Breast Cancer Coalition. Dr. Reginato has served on a series of federal grant review panels, including NIH, DOD, and American Cancer Society (ACS), and is a standing member of the ACS Cell Structure and Metastasis Study Section and NIH-NCI Transition to Independence Study Section. Dr. Reginato has published numerous high impact research articles and has been awarded one US patent.

Members

ABU-KHALAF, MAYSA

BARSEVICK, ANDREA

BERGER, ADAM

BUSSARD, KAREN

BUTRYN, MEGHAN L.

DERMAN, RICHARD E

DIEZ-ROUX, ANA V.

EISENBREY, JOHN

FORMAN, EVAN

HEBER-KATZ, ELLEN

IOZZO, RENATO V.

JASLOW, REBEECCA

JUON, HEE-SOON

KLASSEN, ANN

LOWE, MICHAEL R

MONTI, DANIEL A.

REGINATO, MAURICIO

SCHILDER, RUSSELL

SHAHIN, MARK

SILVER, DANIEL P.

SIMONE, NICOLE