Abstract 3330: BPP, a dual functional inhibitor, targets MLL-rearranged acute myeloid leukemia: Unraveling mechanisms and expanding therapeutic horizons

Abstract

Abstract Refractory/recurrent acute myeloid leukemia (AML) poses a formidable clinical challenge, with MLL translocations implicated in approximately 10% of AML cases and a staggering 75% in infant leukemia, bearing an unfavorable prognosis. Our investigation focuses on BPP, a dual-functional inhibitor capable of inducing DNA cross-linking and suppressing angiogenesis. In a diverse panel of solid tumor and leukemic cells, BPP exhibited exceptional sensitivity against MLL-rearranged AML cell types. In MOLM13 and MV4-11 xenograft models, BPP showcased outstanding tumor suppression, with some tumors even achieving complete remission. In-house acute toxicity testing, BPP treated group showed excellent safety margin in both blood chemistry and pathological examination. Remarkably, BPP demonstrated significant cytotoxicity not only in FLT3-WT AML but also in FLT3-ITD AML. Delving into the mechanism, BPP was found to induce FLT3-ITD and MLL degradation by triggering DNA damage and ER stress. Comet assays revealed a dose-dependent accumulation of DNA fragments in MLL cells upon BPP exposure.The involvement of the KMT2A gene in chromosomal translocation in THP1 cells was highlighted, with BPP treatment resulting in a significant increase in Heat-shock protein. Notably, the combination of ganetespib, an FDA-approved HSP90 inhibitor, with BPP exhibited synergistic effects in both in vitro and in vivo models, inducing synthetic lethality and inhibiting HR repair. Furthermore, BPP not only reduced leukemic stem cells in colony formation assays but also demonstrated sensitivity in relapsed/refractory (R/R) and multiple drug-resistant patient samples. These findings collectively position BPP as a promising candidate for the treatment of MLL-rearranged AML, offering multifaceted therapeutic potential. Citation Format: Tai-Lin Chen, Tsann-Long Su, Te-Chang Lee. BPP, a dual functional inhibitor, targets MLL-rearranged acute myeloid leukemia: Unraveling mechanisms and expanding therapeutic horizons [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3330.