Abstract 653: Enhancing therapies for MYC-overexpressing Non-Hodgkin's lymphoma: A role for MYC downregulation and new combination therapies

Abstract

Background: Non-Hodgkin's Lymphoma (NHL) is the fifth most common cancer in the United States. Up to 40% of NHL is diffuse large B-cell lymphoma (DLBCL); while only 3% of NHL is classified as mantle cell lymphoma, it is a particularly lethal disease. DLBCL and MCL patients that aberrantly express MYC, which occurs up to 20 and 50% of the time, respectively, have worse survival rates and a lack of sustained clinical response to the standard R-CHOP therapy. We sought to examine both the effect of MYC downregulation on the efficacy of standard of care drugs and enhanced anti-cancer activity with a novel NF-kB targeting steroid, in place of prednisone/prednisolone, and also under conditions of MYC modulation, in NHL cells. Methods and Summary of Findings: The downregulation of MYC was achieved in two distinct manners: with siRNA and with our pioneered MYC G-quadruplex (G4)-stabilizing DNA interference (DNAi) oligonucleotide. This DNAi was optimized for stability, specificity, and in cell activity, from our previously work developing this approach (Hao, et al, NAR 2016). The optimization was done using EMSA, chemical (DMS) footprinting, cell viability assays, qPCR, and microscopy. The lead steroid compound, which is selective for NF-κB signaling inhibition over DNA binding and transcription effects, was more cytotoxic than prednisolone, as determined by cell viability assays in NHL cells. Moreover, its effects on cell growth were additive with doxorubicin, and the overall effect of both drugs on cytotoxicity were enhanced by MYC downregulation. The combination studies were also performed with prednisolone; effects on decreased cell viability were more notable with the novel steroid, as compared to prednisolone. Conclusion: MYC-overexpressing NHL, particularly DLBCL and MCL, respond poorly to the standard R-CHOP therapy. The addition of a MYC-downregulating DNAi, a novel NF-kB targeting steroid, or both, have been noted to enhance the cytotoxic effects of standard drugs. Work is expanding to evaluate the utility of an updated R-CHOP regimen in order to enhance survival for patients with MYC-overexpressing NHL. Citation Format: Alexandra Maria Psaras, Tracy Ann Brooks. Enhancing therapies for MYC-overexpressing Non-Hodgkin's lymphoma: A role for MYC downregulation and new combination therapies [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 653.