Abstract 5853: Targeting NAD+/PARP DNA repair pathway as a novel therapeutic approach to SDHB-mutated cluster I pheochromocytoma and paraganglioma

Abstract

Abstract Background: Cluster I pheochromocytomas and paragangliomas (PCPGs) tend to develop malignant transformation, tumor recurrence, and multiplicity. Transcriptomic profiling suggests that cluster I PCPGs and other related tumors exhibit distinctive changes in the tricarboxylic acid (TCA) cycle, the hypoxia signaling pathway, mitochondrial electron transport chain, and methylation status, suggesting that therapeutic regimen might be optimized by targeting these signature molecular pathways. Experimental design: We investigated molecular signatures in clinical specimens from cluster I and II PCPGs, with a focus on the therapeutic resistance mechanisms. Further, we tested the applicability of a combination therapy including an FDA approved PARP inhibitor olaparib (Ola) and temozolomide (TMZ) in both in vitro cellular model and an in vivo allograft animal model. Results: Our findings showed that cluster I PCPGs develop a distinctive dependency on mitochondrial complex I, evidenced by the upregulation of complex I components and enhanced NADH dehydrogenation. Mechanistically, alteration in mitochondrial function resulted in strengthened NAD+ metabolism, which provides essential cofactor for PARP catalytic activity, prompting base excision repair and chemo resistance. Combining PARP inhibitor Ola with TMZ not only improved cytotoxicity but also reduced metastatic lesions, with prolonged overall survival in a mouse model with PCPG allograft. Conclusions: Our results suggest that the NAD+/PARP pathway is a crucial targetable therapeutic resistance mechanism in SDHB-mutated PCPG. Combination therapy using TMZ and Ola could become an effective strategy against these and other advanced cluster I tumors. Disclosure Statement: The authors have nothing to disclose. Citation Format: Ying Pang, Yanxin Lu, Veronika Caisova, Yang Liu, Petra Bullova, Thanh-Truc Huynh, Zdenek Frysak, Igor Hartmann, David Taïeb, Karel Pacak, Chunzhang Yang. Targeting NAD+/PARP DNA repair pathway as a novel therapeutic approach to SDHB-mutated cluster I pheochromocytoma and paraganglioma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5853.