2017 Collaborative Research Development Grant Recipient — Ie-Ming Shih, MD, PhD

Ie-Ming Shih, MD, PhD

Johns Hopkins University School of Medicine

Development of Targeted Therapies for Recurrent Ovarian Cancer

Project Summary

The mortality rates in many major forms of cancer have been reduced over the past decade. However, the mortality rate for ovarian cancer has not been significantly improved. More than three quarters of patients present with advanced stage cancer requiring cisplatin and paclitaxel chemotherapy, and unfortunately, most patients encounter drug resistance and suffer from lack of effective treatment afterwards. There is thus an unmet need to develop new intervention strategies to overcome drug resistance by better understanding its molecular mechanisms. In the past decade, ovarian cancer researchers at Hopkins as at other institutions have focused on delineating the molecular etiology of chemoresistance and recurrence, exploring potential strategies, and developing innovative approaches to treat this devastating disease.

The objective of this development program is to build a research team devoted to creating innovative new treatment modalities to improve clinical outcome and quality of life for ovarian cancer patients. This development program at Johns Hopkins University brings together leaders in ovarian cancer research with the diverse areas of expertise critical for drug development. The program will consist of three projects, each of which will work towards developing new drug treatments. The first project will evaluate an inhibitor for ADRM1, recently identified as a key player in the “ubiquitin-proteasome” system and driver of ovarian cancer. This system controls how proteins are degraded and contributes to regulation of the cell cycle. Our ADRM1 inhibitor directly kills cancer cells, and induces antitumor immunity, thereby targeting recurrent cancer. The second project will evaluate the efficiency of a SYK tyrosine kinase inhibitor, R406 (the active drug of fostamatinib). SYK is a protein that is thought to be critical to ovarian cancer cell survival and proliferation, and inhibition of SYK has been shown to make cells more responsive to paclitaxel-based chemotherapy. The third project will evaluate new PBX1 inhibitors. PBX1 has been found in our previous research to regulate the growth and proliferation of cells with “stem cell-like” features. These cells are self-renewing and resistant to chemotherapy, and they can serve as seeds for the growth of new tumor cells. Inhibiting Pbx1 is thus promising for combating chemoresistance. This program will leverage several shared resources including an Administrative Core, Pharmacology Core, and Mouse Tumor Model Core to facilitate cross-disciplinary collaboration in a cost-effective manner without duplication of efforts individual in individual projects.

This research will allow us to test new and innovative treatment strategies for ovarian cancer, in the hopes of reducing the lethality of this devastating disease. We will leverage the results of these studies to seek larger federal grants and industrial support to propel the clinical development of our promising new therapies.

This grant was made possible in part by a generous donation from the Randall and Barbara Smith Foundation.  

Bio

Richard TeLinde Distinguished Professor of Gynecologic Pathology
Co-Director, Breast and Ovarian Cancer Program
Johns Hopkins University School of Medicine

Dr. Ie-Ming Shih is the Richard TeLinde Distinguished Professor (Endowed Chair) of Gynecologic Pathology and directs this research program at the Johns Hopkins University School of Medicine (1,2). He also co-directs the Breast and Ovarian Cancer Program (3) at the Sidney Kimmel Comprehensive Cancer Center at Hopkins. Dr. Shih received his MD from Taipei Medical University and PhD from the University of Pennsylvania. He is a board-certified pathologist, having completed a clinical fellowship in gynecologic pathology followed by a cancer molecular genetics fellowship at Hopkins. His research focuses on exploring the genomics and pathogenesis of ovarian and endometrial cancer, developing new target-based therapy and applying innovative technology for early detection of gynecologic cancer (2). Dr. Shih’s research laboratory has made several discoveries that contribute to our understanding of the pathogenesis of ovarian cancer, including uncovering the genomic landscapes of different histologic subtypes of ovarian cancer, new mechanisms behind chemoresistance, the tumor suppressor roles of ARID1A, and the possible origin of ovarian high-grade serous carcinoma.

Several researchers in the TeLinde Gynecologic Pathology Research Program and Cancer Center have been devoted to identifying and characterizing potential new molecules that can be exploited to target ovarian cancer. The timely and generous gift from the OCRA allows him to build a research team devoted to developing new treatment modalities to improve clinical outcome in ovarian cancer patients. Dr. Shih has published extensively in the field of ovarian cancer research and served on many advisory and editorial boards. In addition to his clinical, research, and teaching obligations, Dr. Shih is also a passionate photographer (4) who wishes to use his talent to help raise fund for ovarian cancer research.