Harnessing defective DNA repair signaling for the treatment of mantle cell lymphoma

Mantle cell lymphoma (MCL) is a mature B-cell lymphoma characterized by aberrations related to cell cycle dysregulation, DNA damage response and cell survival pathways. In >50% of cases somatic mutations in ATM are observed. Functionally, the kinase ATM is critical for DNA repair, but to date no targeted treatment options exist for this or other high-risk MCL genetic subtypes (i.e.TP53 alterations). Mutational signatures caused by DNA repair deficiencies are further known to shape tumor immune composition. Due to the often aggressive, frequently chemorefractory and fatal disease course, innovative MCL treatments utilizing personalized immunotherapeutic approaches in combination with genetically rationalized agents are urgently needed. We thus aim to identify genetic and proteomic vulnerabilities by targeted and whole-exome sequencing of paired pre- and on-treatment biopsies of high-risk MCL patients. We additionally aim to dissect alternate DNA repair pathways to identify targetable dependencies in ATM-deficient and TP53-mutant MCL in vitro and validate genotype-specific vulnerabilities in in vivo MCL models. The overarching goal of our research is to provide rationale for novel mechanism-based MCL therapies leveraging DNA repair deficiency and incorporating immunotherapy combinations.