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Abstract A07: BTM 3566, a novel activator of the mitochondrial stress response promotes robust therapeutic responses in vitro and in vivo in diffuse large B-cell lymphoma

2022; American Association for Cancer Research; Volume: 3; Issue: 5_Supplement Linguagem: Inglês

10.1158/2643-3249.lymphoma22-a07

2643-3249

Adrian Schwarzer, Matheus Fernandes de Oliveira, Marc‐Jens Kleppa, Andy Anantha, Alan Cooper, Mark Hannink, Todd Hembrough, Jedd Levine, Michael Luther, Michael Stocum, Linsey Stiles, Marc Liesa, Matthew J. Kostura,

Cancer, Hypoxia, and Metabolism

Abstract Relapsed/refractory diffuse large B-cell lymphomas (r/r-DLBCL) are a therapeutic challenge as they are highly heterogeneous both clinically and molecularly, which imposes a pressing need to develop novel therapies to improve outcomes in patients independently of the molecular subtype. We describe here BTM-3566, a first-in-class, orally active compound with activity against DLBCL. BTM-3566 induces apoptosis and complete cell killing in DLBCL lines a with an IC50 of ~200 – 500 nM. Responsive DLBCL cell lines include ABC, GCB, and double-hit and triple-hit lymphoma type. Pharmacokinetic studies in mice showed suitability for once daily dosing, with > 50% oral bioavailability and ~6 hours of serum half-life. In xenograft models using the double-hit DLBCL line SU-DHL-10, BTM-3566 treatment resulted in complete response in all tumor-bearing animals and durable remission in 50% of animals with no tumor growth occurring for 2 weeks after dose cessation. Expansion studies into human DLBCL PDX models harboring a range of high-risk genomic alterations demonstrated response in 100% of the lines with complete response in 6 of 9 PDX models tested. Dose scheduling studies indicate that 7 days of continuous dosing is sufficient to induce tumor regression and maintenance of a complete response. The therapeutic activity of BTM-3566 is related to a novel effect on mitochondrial proteostasis and a robust induction of the ATF4 ISR. Of the four eIF2α -kinases in the human genome we determined that HRI was uniquely required for BTM-3566 activity in DLBCL. HRI is activated by mitochondrial-related stress resulting in activation of the mitochondrial protease OMA1. Molecular analysis revealed that BTM-3566 activates OMA1, leading to induction of the ATF4 ISR pathway and apoptosis in DLBCL cell lines. Deletion of OMA1 reduces the ability of BTM-3566’s to induce apoptosis in DBLCL. Substrates of OMA1 include the dynamin OPA1 and DELE1, a protein recently shown to signal mitochondrial dysfunction through activation of HRI kinase and ATF4. Transfection of BJAB cells with a cleavage resistant OPA1 mutant has no effect on BTM-3566 induced apoptosis. In contrast, DELE1 KO suppresses BTM-3566 mediated apoptosis. BTM-3566 activates OMA1 without acting as a classical mitochondrial toxin. Instead, BTM-3566 induces OMA1 activity through a novel mechanism regulated by the mitochondrial protein FAM210B. FAM210B expression is negatively correlated with response to BTM-3566, and overexpression of FAM210B blocks OMA1 activation and causes complete resistance to BTM-3566 induced apoptosis. Taken together, these data support a novel antitumor mechanism in DLBCL, where BTM3566 induces mitochondrial stress, activating the OMA1-DELE1-HRI-eIF2a-ATF4 pathway leading to apoptosis and tumor regression. An Investigational New Drug application for BTM3566 in B-cell malignancies will be submitted in Q2 2022 with initiation of first in human clinical trials planned for fall 2022. Citation Format: Adrian Schwarzer, Matheus Oliveira, Marc-Jens Kleppa, Andy Anantha, Alan Cooper, Mark Hannink, Todd Hembrough, Jedd Levine, Michael Luther, Michael Stocum, Linsey Stiles, Marc Liesa-Roig, Matthew Kostura. BTM 3566, a novel activator of the mitochondrial stress response promotes robust therapeutic responses in vitro and in vivo in diffuse large B-cell lymphoma [abstract]. In: Proceedings of the Third AACR International Meeting: Advances in Malignant Lymphoma: Maximizing the Basic-Translational Interface for Clinical Application; 2022 Jun 23-26; Boston, MA. Philadelphia (PA): AACR; Blood Cancer Discov 2022;3(5_Suppl):Abstract nr A07.