PARP inhibition has shown promising activity and it is widely used in ovarian cancer (OC). However there is a need to identify novel therapies to enhance the benefit and reverse resistance to PARP inhibition. Macrophages are prominent immune cells in OC tumors and has been shown to induce resistance to therapy and cancer progression. Macrophages with a specific “suppressor” phenotype (M2 subtype) play a significant role in mediating treatment resistance. However, another phenotype (M1 subtype) provides a favorable anti-tumor effect Targeting macrophages and switching them from M2 to M1 is potentially promising approach. In this study, we propose to target them with CD47 inhibition. CD47 is utilized by tumor cells to evade phagocytosis by macrophage and thereby impairs the innate immune response. We pursue a novel combination therapy with anti-CD47 inhibition combined with PARP inhibition to target the macrophages and switch their phenotype. We hypothesize that PARP inhibition resistance in OC may be overcome by targeting immunosuppressive myeloid cells, through a targeted inhibition of CD47 pathway. We aim to demonstrate the macrophage “phenotype switch” within ovarian tumors responding to the combined therapy and reveal unique mechanisms of PARP inhibitors resistance related to targeting this pathway in OC. The potential impact is high as the data generated from this project will provide a rationale to advance a novel treatment option in PARP inhibitor resistant OC.
Dr. Mahdi is an assistant Professor, gynecological oncologist and physician scientist at Magee Women’s hospital and Magee Women’s Research Institute, University of Pittsburgh Medical Center. His research in ovarian cancer was recognized by awards such as V-Foundation Clinical Scholar award, GOG-F scholar award, and K12 Immuno-Oncology scholar award. His research focus is on developmental therapeutics and translational genomic/immune-oncology research in gynecologic cancer specifically ovarian cancer. He is a member of the Developmental Therapeutics, Ovarian Cancer, Translational Science and immunotherapy committees within NCTN/NRG.
As a postdoctoral fellow, he worked in an immunotherapy laboratory to create an immune vaccine using B-cells and to enhance the immune system by depleting T-regulatory cell in patients with solid tumors and leukemia. During fellowship, he worked in Dr. Eng’s laboratory to develop clinical markers to identify uterine cancer patients at risk of harboring Cowden’s syndrome. After fellowship, he received the K12 Immuno-oncology scholar award from 2018-2020 which was focused on investigating the tumor immune micro-environment in ovarian cancer. His research focus has been on developmental therapeutics to identify strategies to overcome therapy resistance and identifying genomic markers to predict response and resistance to immunotherapy and targeted therapy.