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Constitutively Synergistic Multiagent Drug Formulations Targeting MERTK, FLT3, and BCL-2 for Treatment of AML. | LitMetric

AI Article Synopsis

  • High-dose, multiagent chemotherapy has improved survival rates for leukemia, but high-risk cases like infant acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL) still lack effective treatments, creating an urgent need for new therapies.!* -
  • The study tested a combination of the dual MERTK/FLT3 inhibitor MRX-2843 with BCL-2 family protein inhibitors on AML and infant ALL cell lines, using a neural network to predict drug interactions and responses.!* -
  • Results showed that MRX-2843 and venetoclax worked well together to kill AML cells, and the research developed a nanoscale drug delivery system that could improve treatment outcomes by precisely targeting leukemia cells in pediatric

Article Abstract

Purpose: Although high-dose, multiagent chemotherapy has improved leukemia survival rates, treatment outcomes remain poor in high-risk subsets, including acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL) in infants. The development of new, more effective therapies for these patients is therefore an urgent, unmet clinical need.

Methods: The dual MERTK/FLT3 inhibitor MRX-2843 and BCL-2 family protein inhibitors were screened in high-throughput against a panel of AML and MLL-rearranged precursor B-cell ALL (infant ALL) cell lines. A neural network model was built to correlate ratiometric drug synergy and target gene expression. Drugs were loaded into liposomal nanocarriers to assess primary AML cell responses.

Results: MRX-2843 synergized with venetoclax to reduce AML cell density in vitro. A neural network classifier based on drug exposure and target gene expression predicted drug synergy and growth inhibition in AML with high accuracy. Combination monovalent liposomal drug formulations delivered defined drug ratios intracellularly and recapitulated synergistic drug activity. The magnitude and frequency of synergistic responses were both maintained and improved following drug formulation in a genotypically diverse set of primary AML bone marrow specimens.

Conclusions: 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 infant ALL cells. We demonstrate ratiometric drug delivery and synergistic cell killing in AML, a result achieved by a systematic, generalizable approach of combination drug screening and nanoscale formulation that may be extended to other drug pairs or diseases in the future.

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Source
http://dx.doi.org/10.1007/s11095-023-03596-9DOI Listing

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