The implementation of targeted therapies for acute myeloid leukemia has been challenged by complex mutational patterns within and across patients as well as a dearth of pharmacologic agents for most mutational events. Here, we report initial findings from the Beat AML program on a cohort of 672 tumor specimens collected from 562 patients. We assessed these specimens using whole exome sequencing, RNA-sequencing, and ex vivo drug sensitivity analyses. Our data reveal Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:

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Although high-dose, multi-agent chemotherapy has improved leukemia survival rates in recent years, treatment outcomes remain poor in high-risk subsets, including acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL) in infants. Development of new, more effective therapies for these patients is therefore an urgent, unmet clinical need. To address this challenge, we developed a nanoscale combination drug formulation that exploits ectopic expression of MERTK tyrosine kinase and dependency on BCL-2 family proteins for leukemia cell survival in pediatric AML and MLL-rearranged precursor B-cell ALL (infant ALL). In a novel, high-throughput combination drug screen, the MERTK/FLT3 inhibitor MRX-2843 synergized with venetoclax and other BCL-2 family protein inhibitors to reduce AML cell density in vitro. Neural network models based on drug exposure and target gene expression were used to identify a classifier predictive of drug synergy in AML. To maximize the therapeutic potential of these findings, we developed a combination monovalent liposomal drug formulation that maintains ratiometric drug synergy in cell-free assays and following intracellular delivery. The translational potential of these nanoscale drug formulations was confirmed in a genotypically diverse set of primary AML patient samples and both the magnitude and frequency of synergistic responses were not only maintained but were improved following drug formulation. Together, these findings demonstrate a systematic, generalizable approach to combination drug screening, formulation, and development that maximizes therapeutic potential, was effectively applied to develop a novel nanoscale combination therapy for treatment of AML, and could be extended to other drug combinations or diseases in the future.

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While overall outcomes have improved for patients with acute leukemia, high-risk subsets including acute myeloid leukemia (AML) and relapsed/refractory early T-cell precursor acute lymphoblastic leukemia (ETP-ALL) continue to have poor prognosis. New therapies are urgently needed. Both MERTK tyrosine kinase and the anti-apoptotic protein BCL-2 have been implicated as therapeutic targets in AML and ETP-ALL. We developed MRX-2843, a novel small molecule MERTK and FLT3 inhibitor currently in clinical trials in patients with leukemia. The BCL-2 inhibitor venetoclax is FDA-approved for treatment of AML and has clinical activity in relapsed/refractory T-ALL. Here, we investigated the impact of treatment with MRX-2843 in combination with BCL-2 inhibitors in preclinical models. Human AML and ETP-ALL cell lines were treated with MRX-2843 and/or a BCL-2 inhibitor for 48-72 hours and relative cell numbers were determined using CellTiter-Glo reagent. Synergy was assessed by mathematical modeling using the response additivity and fractional product methods. Combined treatment with MRX-2843 and venetoclax provided enhanced therapeutic efficacy compared to MRX-2843 or venetoclax alone. The interaction between drugs was dose-dependent and synergistic in AML cell lines. For instance, in KG-1 cells combined treatment with an IC50 concentration of MRX-2843 and an IC15 concentration of venetoclax reduced cell density by 88 ± 4.0% and the combination was significantly more effective than MRX-2843 or venetoclax alone (p < 0.0001, 2-way ANOVA). Moreover, the 88% reduction in cell density in cultures treated with the combination was significantly greater than the 58 ± 1.6% reduction expected for an additive interaction (p < 0.0001). Robust therapeutic activity and dramatic synergy were also observed in NOMO-1 and OCI-AML5 cell cultures treated with the combination and the interaction between drugs was additive or synergistic in Loucy ETP-ALL cells. Enhanced therapeutic efficacy and synergistic interactions were also observed in AML cell cultures treated with MRX-2843 and navitoclax, a BCL-2 and BCL-XL inhibitor, implicating BCL-2 inhibition as a mechanism of synergy. In a high-throughput screen, MRX-2843 mediated synergistic anti-leukemia activity in combination with venetoclax in all 7 AML and both ETP-ALL cell lines tested. Synergy was optimal when MRX-2843 and venetoclax were administered in a 1:20 ratio. Our data (i) implicate combined treatment with MRX-2843 and a BCL-2 inhibitor, such as venetoclax, as a promising new strategy for treatment of both AML and ETP-ALL, (ii) define optimized dosing strategies for MRX-2843 and venetoclax combination therapy, and (iii) support further evaluation of MRX-2843 in combination with venetoclax in murine models and potentially in upcoming clinical trials. Citation Format: Aashis Thapa, Juhi Jain, Ryan J. Summers, James M. Kelvin, Xiaodong Wang, Stephen V. Frye, H. Shelton Earp, Erik C. Dreaden, Deborah DeRyckere, Douglas K. Graham. MRX-2843, a dual MERTK and FLT3 inhibitor, mediates synergistic anti-leukemia activity in combination with BCL-2 inhibitors in acute myeloid leukemia and early T-cell precursor acute lymphoblastic leukemia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3339.