Proteogenomic characterization of early and late resistance mechanisms in acute myeloid leukemia

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PROJECT SUMMARY/ABSTRACT Acute myeloid leukemia (AML) is one of the most common hematologic malignancies, representing a diverse collection of complex diseases. After 30-40 years without change of treatment strategy, the past 2 years have seen several drug approvals, including recent approvals for the FLT3 inhibitor, gilteritinib, and the BCL2 inhibitor, venetoclax. While response rates to both of these agents are encouraging, drug resistance and relapse is still problematic for nearly all patients. For the past decade, we have executed a functional proteogenomics platform applied directly to primary samples from patients with AML and other hematologic malignancies. Using this platform, we have collectively studied over 2,500 primary patient specimens. Through integration of these data with expansive proteomic, phospho-proteomic, transcriptomic, genomic, metabolomic, genome-wide CRISPR screens, and detailed clinical annotations, we have defined biomarkers and mechanisms underlying response as well as early and late resistance to both FLT3i and BCL2i. Consequently, we have started clinical trials testing combinations that may mitigate these resistance mechanisms. For this project, our long-term goals are to translate FLT3i and BCL2i therapeutic regimens such that resistance can be prevented with up-front combinations and/or mitigated with sequential therapies. Our immediate goals are to define and optimize specific biomarkers of response and resistance to these agents. Based on the central hypothesis that examination of global proteomic features of AML provides predictors of drug response and also identifies the dynamic changes during development of drug resistance, yielding mechanistic insight to generate novel, improved drug combinations. To accomplish these goals, Preclinical and Clinical work is proposed: Training of proteogenomic biomarkers on cell line models of early and late resistance – We will perform proteogenomic analyses of a panel of cell lines that have been derived to exhibit drug resistance resembling clinical features of resistance. Validation of signatures in archival patient sample material – We have a substantial biorepository of specimens from AML patients, a subset of which are from patients treated with FLT3i or BCL2i as standard-of-care or as part of our ongoing clinical trials. We will test our cell line derived biomarkers in these banked patient specimens, and we will also use cutting edge proteomics technology that enables low input material to study fractionated cell populations. Clinical validation of biomarkers of sensitivity and resistance – We have opened clinical trials testing FLT3i and BCL2i combinations in AML. We will have access to prospective, longitudinal specimens from patients on these trials. We will perform proteogenomic analyses on these prospective specimens to evaluate the ability of our signatures to predict clinical responses. Cumulatively, we expect these innovative analyses to have a major impact on our understanding of AML biology, with successful clinical translation of new, more effective drug combination strategies and predictive biomarkers.