For questions about this event, please reach out to Veronica Lemme lemmev@health.missouri.edu.

“Pharmacological activation of the mitochondrial stress response in B-cell lymphoma”

Speaker: Dr. Mark Hannink, Professor of Biochemistry; Associate Director, Bond Life Sciences Center

Date: Nov. 17, 2022, 4:30-5:30 p.m.

Description

Diffuse Large B-Cell Lymphomas (DLBCL) are aggressive, rapidly proliferating tumors that critically depend on the ATF4-mediated integrated stress response (ISR) to survive various stresses associated with uncontrolled growth, including hypoxia, amino acid deprivation and accumulation of misfolded proteins. Recent work, done in collaboration with Bantam Pharmaceutical and several academic collaborators, has revealed that ISR hyperactivation is a targetable liability in DLBCL. A novel class of compounds, represented by BTM-3528 and BTM-3566, have been identified that activate the ISR though the mitochondrial protease OMA1. Treatment of tumor cells with compound leads to OMA1-dependent cleavage of DELE1 and OPA1, mitochondrial fragmentation, activation of the eIF2α-kinase HRI, cell growth arrest and apoptosis. Activation of OMA1 by BTM-3528 and BTM-3566 is mechanistically distinct from inhibitors of mitochondrial electron transport, as the compounds induce OMA1 activity in the absence of acute changes in respiration. We further identify the mitochondrial protein FAM210B as a negative regulator of BTM-3528 and BTM-3566 activity. Overexpression of FAM210B prevents both OMA1 activation and apoptosis. Notably, FAM210B expression is nearly absent in healthy germinal-center B-lymphocytes and in derived B-cell malignancies, revealing a fundamental molecular vulnerability that is targeted by BTM compounds. Both compounds induce rapid apoptosis across diverse DLBCL lines derived from activated B-cell, germinal center B-cell and MYC rearranged lymphomas. Once-daily oral dosing of BTM-3566 resulted in complete regression of xenografted human DLBCL SU-DHL-10 cells and complete regression in 6 of 9 DLBCL patient-derived xenografts. Selective constitutive activation of the mitochondrial ISR represents a novel therapeutic approach for treating DLBCL tumors.