Abstract A036: Amplifying B-cell lymphoma apoptosis by targeting two oncoproteins with a new bispecific compound

Abstract

Aggressive B-cell lymphomas have significantly high relapse/refractory rates of 20-40%, and outcomes in these patients are very poor, warranting an urgent need for novel, more targeted therapeutic strategies. Using a combination of biological and biochemical approaches, we identified a previously unknown, targetable vulnerability in diffuse large B-cell lymphoma (DLBCL) and Burkitt lymphoma, including those with genetic alterations that lead to more aggressive and challenging to treat disease, such as p53 mutations and MYC overexpression with/without BCL2 overexpression. With a new bispecific compound, we target two oncoproteins, both of which are overexpressed in B-cell lymphomas, and observed high efficacy with apoptosis induction. The targeted bispecific compound binds to two oncoproteins and promotes their degradation, leading to activation of the p53 family member, p73, in p53 mutant lymphomas and apoptosis of cell lines and patient samples. Moreover, loss of the oncoproteins with the bispecific compound in vivo effectively reduces tumor volumes and significantly extends survival of mice with DLBCL and Burkitt lymphoma xenografts. We further evaluated the mechanism by which the bispecific compound promotes p73-mediated lymphoma cell death. Prior to apoptosis, caspase-independent DNA double-strand breaks and DNA damage signaling, the stimuli for p73 activation and apoptosis, was observed. Our data underscore dual targeting of two oncoproteins as a novel vulnerability with treatment potential for aggressive B-cell lymphomas. Our results also yield important insights into DNA instability in rapidly growing lymphomas that could be further exploited.