Activating mutations in tyrosine kinase are common in human myeloid malignancies. Our long-term goal is to improve outcomes in patients with myeloid malignancies through basic and translational studies. FLT3 is the most commonly mutated gene in acute myeloid leukemia (AML). The objective of this grant is to build upon recent advances in medicinal chemistry that are pushing the boundaries of targeted therapeutics, to further inform kinase and disease biology, and to override evolving mechanisms of on- and off-target resistance to these agents. The central hypothesis is that basic and translational studies employing state-of-the-art molecular tools to interrogate clinically-relevant models of resistant disease will inform novel therapeutic approaches and advance our understanding of human leukemia biology. Our rationale is that pioneering work on BCR-ABL1 in chronic myeloid leukemia represents a paradigm that can successfully be applied to other myeloid malignancies. Previously, we provided compelling evidence validating activated FLT3 as a therapeutic target in human AML. This work rekindled efforts to develop potent and selective FLT3 kinase inhibitors that minimize vulnerabilities to resistance-conferring secondary kinase domain mutations in FLT3-ITD and led to the recent approval of gilteritinib. However, gilteritinib causes myelosuppression that limits its utility. Our preclinical work nominated activating RAS mutations as potential mediators of off-target resistance, and our recent translational studies of patients treated with gilteritinib have confirmed activated RAS as the dominant mechanism of acquired resistance to this drug. We propose to develop best-in-class FLT3 tyrosine kinase inhibitors (TKIs) that are impervious to on-target resistance mutations and devoid of hematologic toxicity. We further propose studies to identify and exploit vulnerabilities in NRAS-mutant FLT3-ITD-positive AML cells.
Our specific aims will test the following hypotheses:
(Aim 1) That potent and selective FLT3 inhibitors will have a sufficient therapeutic index to enable them to retain activity against common secondary kinase domain mutants and will be devoid of hematologic toxicity;
(Aim 2) That coexistence of pathologically activated FLT3 and NRAS will create novel dependencies that can be exploited therapeutically;
and (Aim 3) That structural studies and compound optimization can identify active compounds with drug-like properties. Upon conclusion of these studies, we will have a more detailed understanding of chemical scaffolds that potently and selectively target FLT3, novel understanding of AML cells that contain co-existent FLT3-ITD and NRAS mutations, insights into therapeutic vulnerabilities in this setting, and novel therapeutics. This contribution is significant since it has the potential to rapidly impact clinical investigation and therapeutic outcomes. The proposed research is innovative because it proposes application of state-of-the-art methodologies to systematically probe the molecular underpinnings of AML resistant to targeted therapeutics, and combine them with expertise in chemical structural biology. This work is potentially highly impactful as AML remains associated with a poor prognosis.
The proposed research is relevant to the public health because acute myeloid leukemia represents a major national cost measured by both patient suffering, diminished years of life, and economic burden. Despite recent advances in drug development, clinical trial data demonstrate that a minority of acute myeloid leukemia patients are cured, and the majority succumb to their disease, typically within two years following diagnosis. Upon conclusion, we will likely have two potential treatment options that have significant promise for effectively preventing/treating the two most common mechanisms of resistance to potent FLT3 inhibitor therapy, and which are expected to forestall or prevent disease relapse and improve outcomes in a subset of AML patients substantially.
