Adaptive responses in a PARP inhibitor window of opportunity trial illustrate limited functional interlesional heterogeneity and potential combination therapy options

Abstract

// Marilyne Labrie 1 , Tae-Beom Kim 2 , Zhenlin Ju 2 , Sanghoon Lee 3 , Wei Zhao 3 , Yong Fang 1 , Yiling Lu 3 , Ken Chen 2 , Pedro Ramirez 4 , Michael Frumovitz 4 , Larissa Meyer 4 , Nicole D. Fleming 4 , Anil K. Sood 4 , Robert L. Coleman 4 , Gordon B. Mills 1 , 3 and Shannon N. Westin 4 1 Knight Cancer Institute and Cell, Developmental and Cancer Biology, Oregon Health and Science University, Portland, OR, USA 2 Department of Bioinformatics and Computational Biology, University of Texas, MD Anderson Cancer Center, Houston, TX, USA 3 Department of Systems Biology, University of Texas, MD Anderson Cancer Center, Houston, TX, USA 4 Department of Gynecologic Oncology and Reproductive Medicine, University of Texas, MD Anderson Cancer Center, Houston, TX, USA Correspondence to: Shannon N. Westin, email: swestin@mdanderson.org Keywords: poly (ADP-ribose) polymerase inhibitor; combination therapy; adaptive response; ovarian cancer; targeted therapy Received: March 12, 2019     Accepted: May 02, 2019     Published: May 28, 2019 ABSTRACT Poly (ADP-ribose) polymerase inhibitor (PARPi)-based combination therapies are demonstrating efficacy in patients, however, identifying the right combination for the right patient remains a critical challenge. Thus, it is urgent to develop approaches able to identify patients likely to benefit from specific combination therapies. Several groups, including ours, have demonstrated that targeting adaptive responses induced by PARPi increases depth and duration of response. In this study, we instituted a talazoparib (PARPi) monotherapy window of opportunity trial to identify informative adaptive responses in high grade serous ovarian cancer patients (HGSOC). Patients were treated for 7 to 14 days with PARPi monotherapy prior to surgery with tissue samples from multiple sites being collected pre- and post-treatment in each patient. Analysis of these samples demonstrated that individual patients displayed different adaptive responses with limited interlesional heterogeneity. Ability of combination therapies designed to interdict adaptive responses to decrease viability was validated using model systems. Thus, assessment of adaptive responses to PARPi provides an opportunity for patient-specific selection of combination therapies designed to interdict patient-specific adaptive responses to maximize patient benefit.