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|Authors||Priyanka Somanath; Daniel Lu; Brian Law; James T. Palmer; Taisei Kinoshita; Mini Balakrishnan; Thomas Butler|
|Title||Anti-tumor activity of irreversible menin inhibitor, BMF-219, in high-grade B-cell lymphoma and multiple myeloma preclinical models|
|Date||June 15, 2022|
|Abstract Text||Double/Triple Hit Lymphoma (DHL/THL) and Double Expressor Lymphoma (DEL) are high-grade B-cell lymphomas (HGBCL) that exhibit low responses to standard therapeutic regimens resulting in poor prognosis. DHL harbor translocations in MYC and BCL2 or BCL6, THL contain translocations in MYC/BCL2/BCL6, and DEL are characterized by high expression of MYC and BCL2. Menin is a scaffold protein that drives oncogenic function through its regulation of genes such as HOXA9, with distinct effects on transcription that are directed by various cofactors. A recent study reported that knockdown of HOXA9 resulted in marked growth inhibition of multiple myeloma (MM) cells (Chapman et al., 2017). We previously reported the ability of irreversible menin inhibitor, BMF-219, to modulate MYC expression and exhibit high potency against DHL DLBCL preclinical models. Moreover, we demonstrated that MYC and its co-factor MAX, regulate differential gene expression in BMF-219-treated leukemia cells. Here, we demonstrate the anti-tumor activity of BMF-219 in HGBCL and MM preclinical models harboring various mutational backgrounds. BMF-219 exhibited high potency against THL and DEL cell lines, with IC50 values of 0.27 μM and 0.37 μM, respectively. Both models achieved >90% growth inhibition with single-agent treatment. Notably, BMF-219 was multi-fold more potent and exerted dramatically greater growth inhibition compared to clinical reversible menin inhibitors in all DLBCL cell lines tested, including an expanded panel of DHL cell lines. In ex vivo studies, an R-CHOP refractory THL patient sample and an R-EPOCH refractory MYC-amplified DLBCL patient sample were highly sensitive to BMF-219 treatment, with IC50 values of 0.15 μM and 0.2 μM, respectively, and demonstrated complete growth inhibition at 1 μM exposure. In contrast, two clinical reversible menin inhibitors demonstrated much lower potency (IC50 = 0.96 μM and 6.3 μM in the MYC-amplified model, and IC50 = 5.63 μM and not calculable for the second reversible inhibitor in the THL model). MM cell lines harboring mutations in TP53, KRAS and NRAS were all sensitive to BMF-219 with IC50 values in the range of 0.25 μM to 0.5 μM and achieved 100% growth inhibition at 1 μM exposure. Combination treatments of BMF-219 with standard-of-care agents in MM cell lines were also tested. Notably, BMF-219 demonstrated single-agent efficacy (IC50 values between 0.1 μM and 0.3 μM) against a panel of newly diagnosed and R/R ex vivo MM samples, including a p53-deleted clinical profile. Collectively, our data demonstrate the novel and robust anti-tumor activity of BMF-219 in HGBCL and MM preclinical models that represent categories of high unmet need. BMF-219 exhibits multi-fold higher potency and complete growth inhibition in these preclinical models compared to clinical reversible menin inhibitors, demonstrating its unique anti-tumor potential in these cancers.|
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|NRAS act mut||multiple myeloma||predicted - sensitive||BMF-219||Preclinical - Cell culture||Actionable||In a preclinical study, BMF-219 inhibited growth of multiple myeloma cell lines harboring NRAS activating mutations in culture (Cancer Res 2022;82(12_Suppl):Abstract nr 2654).||detail...|