Identify the Mechanisms of LMO2-Mediated Inhibition of Homologous Recombination and Establish PARP-Targeted Synthetic Lethality as a New Therapy for DLBCL

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PROJECT SUMMARY/ ABSTRACT Diffuse large B-cell lymphoma (DLBCL) is the most common subtype of non-Hodgkin lymphoma (NHL), with ~25,000 new cases yearly. Despite marked improvement in therapy, about half of these patients succumb to their disease. Therefore, there is a strong need for new therapeutic approaches to improve DLBCL patients' survival. Here we show that in DLBCL cells the LIM domain-only 2 (LMO2) protein inhibits DNA double-strand break (DSB) repair via homologous recombination (HR), resulting in HR-dysfunction. This HR-dysfunction phenocopies BRCA1/2 mutations in breast, ovarian and castration-resistant prostate cancers. Accordingly, we show that LMO2 predisposes DLBCL cells to synthetic lethality upon treatment with Poly(adenosine diphosphate ribose) polymerase 1 and 2 (PARP1/2) inhibitors. The long-term goal is to demonstrate that PARPi activity may improve outcome of patients with LMO2 expressing DLBCL. The overall objectives of this proposal are to determine the mechanisms by which LMO2 inhibits the repair of DNA breaks via HR and whether LMO2 expression levels can be exploited as a biomarker for sensitivity of DLBCL to PARP1/2 inhibitors. The central hypothesis is that inhibition of DNA repair via HR induced by LMO2 will sensitize DLBCL tumors to PARP1/2 inhibitors. The rationale for this project is that deficiency in HR and failure to repair DSBs produced cause solid during replication Indeed, PARP1/2 inhibitors that the accumulation of toxic DSBs during replication, had been exploited for the treatment of HR-deficient tumors. can lead to genomic instability and/or cell death. Our preliminary data showed that in DLBCL cells LMO2 inhibits the HR pathway. Thus, we propose that inhibition of HR by LMO2 will sensitize DLBCL tumors to PARP1/2 inhibitors. In order to test the central aims : hypotesis and determine the mechanims by which LMO2 controls DNA repair we propose three specific 1)Identify mechanism(s) of LMO2-mediated inhibition of HR in DLBCL; 2) Determine how LMO2 affects immunoglobulin class switch recombination in normal B-cells; and 3) Demonstrate that DLBCL expressing LMO2 are sensitive to PARP1/2 inhibition. The proposed research is innovative because it represents a substantive departure from the current status quo by demonstrating that expression of LMO2 protein predicts therapeutic activity of PARP1/2 inhibitors in DLBCL and represents an effective new therapeutic strategy that will broaden the existing arsenal against this lymphoma. The research proposed is significant because it is expected to provide strong scientific justification for the development of a novel therapeutic approach for DLBCL based in PARP1/2 inhibitors that could potentially change the current treatment of DLBCL patients and improve their outcome.