Abstract IA22: Systems approach to rational combination therapy

Abstract

Abstract Tumors evolve under therapeutic pressure both through rapid epigenomic mechanisms primarily at the protein network level and long-term genomic evolution. The realization of the promise of personalized molecular medicine will require efficient development and implementation of effective combination therapies able to capitalize on or interdict tumor evolution under therapeutic pressure. While we are beginning to develop a series of biomarkers able to predict which patients will benefit from monotherapy, our ability to predict which combination therapies will be active in particular patients is in its infancy. Integration of spatially oriented DNA, RNA, and protein information content as they change under therapeutic pressure has the potential to help identify patients likely to respond to combination therapy. Therapy resistance can be pre-existing, adaptive, or acquired. Resistance can also occur through a heterogeneity of molecular changes within the tumor and metastases. Adaptive resistance, which is the consequence of activation of homeostatic loops and phylogenetically conserved stress responses, provides a potential therapeutic liability that can be leveraged for rational combinatorial therapy. Thus, a comprehensive analysis of patient tumors before, during, and after treatment should become the standard of practice to enable identification of mechanisms of resistance as well as to allow rapid evolution of patient therapy. Testing these precepts will require the development and implementation of novel biopsy-driven trial designs and CLIA-compliant analytics that can be deployed in real time to allow rapid evolution of therapeutic approaches. We have implemented a suite of biopsy-driven trials linked to deep molecular analysis with the goal of rapid identification of tumor evolution to enable change in therapy to counter tumor evolution as it arises. We have implemented a series of studies based on PARP inhibitors as a backbone with the goal of increasing the depth and duration of response while at the same time extending the population of patients who benefit beyond those with homologous recombination defects. Concurrently, we have a series of n-of-one studies with combinations of FDA-approved drugs. Early data suggest that these approaches have the potential to greatly improve patient outcomes. Citation Format: Gordon B. Mills. Systems approach to rational combination therapy [abstract]. In: Proceedings of the AACR Special Conference on the Evolving Landscape of Cancer Modeling; 2020 Mar 2-5; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2020;80(11 Suppl):Abstract nr IA22.