Translating Improved Pairing and Timing of Drug Combination Strategies

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PROJECT SUMMARY: Project 3 The goal of this Project is to translate newly discovered mechanisms of acquired drug resistance in acute myeloid leukemia (AML) from Projects 1 and 2 into novel drug combinations that can be deployed early in disease evolution to prevent disease relapse and improve patient outcomes. Disease relapse in AML is fueled by a complex cross-talk of tumor cells adapting with support from the bone marrow microenvironment. Our prior work, which was conducted by Leads and Personnel in this Project collaborating closely with Projects 1 and 2 as part of the OHSU DRSN U54 – the predecessor to ARTNet – has shown that acquired drug resistance in AML proceeds via a multi-stage process. Early resistance is driven by cell state changes stimulated from tumor- extrinsic signals, and this early resistance eventually transitions to a late stage of resistance with features of clonal evolution. Understanding this process creates immediate translational opportunities for intervention during the early stage of resistance. Indeed, our work from the DRSN Center has already led to novel drug combinations that have been translated into clinical to mitigate resistance to important new therapies for AML, such as FLT3 and BCL2 inhibitors. This prior work has led to a central hypothesis that delineation of pathways driving early detection of drug resistance will lead to the development of improved drug combinations, at the earliest time possible, to overcome resistance and improve patient outcomes. For this project, our immediate goals are to prioritize the most promising drug combinations and most reliable resistance signatures for clinical translation. To accomplish these goals, three Aims are proposed: 1) Evaluate signatures of resistance using primary AML samples in ex vivo assays: We will use our long-standing expertise of testing primary AML patient samples against drug combinations using both high-throughput screening platforms, imaging and flow-based readouts to evaluate phenotypic effects in single-cells, and an advanced, 3D model of the bone marrow microenvironment that facilitates long-term drug testing of primary patient samples (Humarrow). 2) Longitudinal evaluation of samples from patients receiving rational therapeutic regimens: We will perform detailed characterization of longitudinal specimens from patients enrolled on our cutting-edge combination therapy clinical trials to evaluate signatures of resistance at early stages of therapy. 3) Employ sensitive detection techniques to detect low levels of resistance in primary samples: We will use single-cell and cell enrichment analytical techniques in specimens from newly diagnosed and early-stage AML patients to define the earliest point at which resistance signatures can be detected. All of these data will inform and refine the work of Projects 1 and 2 and will be leveraged to support the development of future clinical trials and clinically- informative signatures of acquired drug resistance. Collectively, this work will identify new regimens to treat patients at the earliest possible stage, thereby, preventing disease relapse and improving durable outcomes.