Determining Biomarkers of Response and resistance to Venetoclax and Azacitadine

About This Grant

PROJECT SUMMARY/ABSTRACT Background: The combination of hypomethylating agent (HMA) and the BCL2 inhibitor venetoclax (venHMA) has become the new standard of care for newly diagnosed older patients with acute myeloid leukemia (AML). However, one third of patients do not respond and the remainder of patients inevitably relapse on therapy in the absence of stem cell transplant. Biomarkers to predict response to venHMA are limited and clinical relapse mechanisms remain poorly characterized. No proven therapy exists for the majority of patients who relapse after treatment with venHMA. Rationale: To develop effective therapies to prevent and treat relapse, improved understanding of the molecular mechanisms underlying primary and secondary resistance to venHMA is required. A comprehensive study of samples from AML patients who are treated in both clinical trial and realworld settings is the best mechanism by which to derive clinically relevant biomarkers of response and resistance. Methods: We will perform integrated bulk and single cell molecular characterization of samples from patients treated on a large multi-center clinical trial of venHMA in older patients with AML to develop biomarkers of clinical response and determine mechanisms of acquired resistance. We will perform confirmatory sequencing studies in patients similarly treated in a real-world setting. Moreover, we will perform mechanistic validation studies of putative clinical resistance mechanisms in genotype-matched AML cell lines in vitro and in vivo in patient derived xenografts (PDXs). The use of in vivo PDX models will allow us to validate resistance mechanisms and test a clinically actionable therapeutic strategy of RAS inhibition in the most patient-relevant model system. Expected Results: We anticipate that this work will uncover critical insights about clinically relevant mechanisms of response and resistance to venHMA. The overall goal of this work is to develop clinically relevant biomarkers to guide the treatment of AML patients and to facilitate the development of new treatment strategies for refractory/relapsed AML, a group of patients with no current standard of care.