Abramson Cancer Center Director’s Leadership Council March 13, 2017 “Bringing the Noise: Changing the Face of the Silent Killer” Gynecologic Oncology Program Ronny Drapkin, MD, PhD Director, Penn Ovarian Cancer Research Center Director, Gynecologic Oncology Research, Basser Center for BRCA Robert Burger, MD Director, Clinical Research Mark Morgan, MD Chief, Gynecologic Oncology 1

Ovarian Cancer – The ‘Silent’ Killer 10 20 30 40 50 60 70 80 90 % 5-year survival 1 2 3 4 Clinical Stage There are 240,000 new cases of ovarian cancer diagnosed each year 152,000 deaths/yr 70-80 % of women are diagnosed with late stage disease Lack of screening tool for early detection Limited understanding of molecular pathogenesis Most lethal gynecologic malignancy Tumor Basic overview of clinical scenario

Why Penn? Unique commitment to Gynecologic Cancers Penn Ovarian Cancer Research Center - 2007 Basser Center for BRCA – 2012 Collaborators across other Philadelphia-based institutes Collaborative environment Why study ovarian cancer at Penn. Why did I come here from Harvard. “In the long history of humankind (and animal kind, too) those who learned to collaborate and improvise most effectively have prevailed.” Charles Darwin On the Origin of Species, 1859

Goals of Ovarian Cancer Research Center (OCRC) Develop a comprehensive understanding of ovarian cancer pathogenesis. Develop new methods for early detection and prevention of ovarian cancer. Characterize the genetic factors that drive the development of hereditary (BRCA) and sporadic forms of ovarian cancer. Develop new approaches to treat and prevent ovarian cancer. Support clinical trials to assess safety and efficacy of new treatments. The ultimate goal of these programs is to improve the quality of life for women with ovarian cancer and provide guidance and support to their families.

BRCA as a Model for Early Ovarian Cancer Opportunity to evaluate the tubes and ovaries in women who undergo prophylactic salpingo-oophorectomy and detect tumors early in their course But the prophylactic removal of the tubes and ovaries in women with BRCA mutations afforded pathologists an opportunity to carefully examine these tissues for occult cancer, cancers that were not clinically evident. And in a series of studies that span about 6 years while I was at the Dana-Farber Cancer Institute in Boston, we found that most SEROUS ovarian cancers actually arise from the fallopian tube epithelial cells, not the ovary. This observation has now been reproduced in centers around the world and it has become generally accepted that the fallopian tube is the site of origin. This paradigm shift has had tremendous impact on our approaches to early detection (we’ve been looking in the wrong place for a long time), prevention (can we consider just removing the fallopian tubes and spare women the surgical menopause that they are put into with the combined surgery? An area of active debate), and defining new therapeutic targets. “Ovarian Cancers” actually start in the Fallopian Tube, not the Ovary!

Impact of Fallopian Tube Prevention: Remove tissue at risk  complications: “Surgical menopause” SGO recommendation for women at risk: Two-step risk reduction Recommendation for women at average risk: Opportunistic salpingectomy at time of hysterectomy, in lieu of tubal ligation, other pelvic surgery Early Detection: CA125: inadequate for early detection Transvaginal Ultrasound: inadequate for early detection New BINARY biomarkers for ovarian cancer

Perets and Drapkin, Cancer Res, 2016

Gyn Oncology Immunotherapy CAR T-Cell Therapy Trials: Mesothelin Folate Receptor Vaccine Trials: Survivin Chemo + Checkpoint inhibitors: Ab against PD-L1 (Avelumab) Ab-drug conjugate against Folate Receptor Dual checkpoint inhibitors Janos Tanyi, Dan Powell, Robert Burger

Penn Ovarian Cancer Research Center PDX Platform Primary Orthotopic PDX model with patient-matched immunity PI: F. Simpkins lab Metastatic Orthotopic PDX models PI: R. Drapkin lab George et al., JCI Insight, 2017 Liu et al., CCR, 2017

Volume of GYN Biospecimens Tumor type HUP PAH CCH Penn Med-Virtua Ovarian 80 35 20 emerging Endometrial 100 90 Cervix 40 25 10 Other 30 Penn Medicine Virtua in Lumberton, NJ

Rationale Evidence-Based MAINtenance (REMAIN) BIOmarkers for Diagnosis Treatment Recurrence Death Rapid Autopsy Program (RAP) Rationale Evidence-Based MAINtenance (REMAIN) BIOmarkers for Ovarian Cancer (BioOvCa) LONGitudinal Genomic PROFILing (LONG PROFILE) PDX-Assisted THerapeutics FOR Women At Recurrent Disease (PATH FORWARD) OCRC Tumor Bank

? BRCA New Models Clinical Trials ncRNAs Pathogenesis Biomarkers CAR T-Cell Therapy Tumor Immunology Blood Vessels Vaccines ? ncRNAs Pathogenesis BRCA New Models Clinical Trials

….we have to build bridges.

This is a photo of a corn silo in Iowa that I took during a recent visit. Silos are great for storing food and when it comes to science, that is about it. Silos have no place in the modern biomedical research area. We can’t work alone. No one has the resources to address the vexing problems of cancer biology alone and even if you did you couldn’t possible attack the problem from multiple angles. Instead…..