Mp28-15 a new strategy to enhance cisplatin efficacy while reducing nephrotoxicity through targeted neddylation inhibition

You have accessJournal of UrologyCME1 Apr 2023MP28-15 A NEW STRATEGY TO ENHANCE CISPLATIN EFFICACY WHILE REDUCING NEPHROTOXICITY THROUGH TARGETED NEDDYLATION INHIBITION Kyle Garcia, Trace Jones, Claudia Espitia, Juan Chipollini, Benjamin Lee, Jason Wertheim, Jennifer Carew, and Steffan Nawrocki Kyle GarciaKyle Garcia More articles by this author , Trace JonesTrace Jones More articles by this author , Claudia EspitiaClaudia Espitia More articles by this author , Juan ChipolliniJuan Chipollini More articles by this author , Benjamin LeeBenjamin Lee More articles by this author , Jason WertheimJason Wertheim More articles by this author , Jennifer CarewJennifer Carew More articles by this author , and Steffan NawrockiSteffan Nawrocki More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000003256.15AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Although cisplatin remains a backbone of standard of care chemotherapy regimens for a variety of malignancies, its use is often associated with severe dose-limiting toxicities (DLT). Notably, 30-40% of patients treated with cisplatin-based regimens are forced to discontinue treatment after experiencing nephrotoxicity as a DLT. New approaches that simultaneously prevent renal toxicity while improving therapeutic response have the potential to make a major clinical impact for patients with multiple forms of cancer. Here, we report that pevonedistat (MLN4924), a first-in-class NEDDylation inhibitor, alleviates nephrotoxicity and synergistically enhances the anticancer efficacy of cisplatin in head and neck squamous cell carcinoma (HNSCC) models METHODS: The effects of pevonedistat and cisplatin on normal renal proximal epithelial cells were evaluated using in vitro and in vivo models. Molecular and biological experiments were performed to investigate the cytoprotective effects of pevonedistat from cisplatin-mediated nephrotoxicity. RESULTS: We demonstrate that pevonedistat protects normal kidney cells from injury while enhancing the anticancer activity of cisplatin through a thioredoxin interacting protein (TXNIP)-mediated mechanism. Co-treatment with pevonedistat and cisplatin yielded dramatic HNSCC tumor regression and long-term animal survival in 100% of treated mice. Importantly, the combination decreased nephrotoxicity induced by cisplatin monotherapy as evidenced by the blockade of kidney injury molecule-1 (KIM-1) and TXNIP expression, a reduction in collapsed glomeruli and necrotic cast formation, and inhibition of cisplatin-mediated animal weight loss. CONCLUSIONS: Inhibition of NEDDylation represents a novel strategy to prevent cisplatin-induced nephrotoxicity while simultaneously enhancing its anticancer activity through a redox-mediated mechanism. A clinical trial further investigating the safety and efficacy of this approach is being planned. Source of Funding: Research reported in this publication was supported by the National Cancer Institute of the National Institutes of Health under award numbers T32CA009213, R01CA268383, R01CA190789 and P30CA023074 © 2023 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 209Issue Supplement 4April 2023Page: e377 Advertisement Copyright & Permissions© 2023 by American Urological Association Education and Research, Inc.MetricsAuthor Information Kyle Garcia More articles by this author Trace Jones More articles by this author Claudia Espitia More articles by this author Juan Chipollini More articles by this author Benjamin Lee More articles by this author Jason Wertheim More articles by this author Jennifer Carew More articles by this author Steffan Nawrocki More articles by this author Expand All Advertisement PDF downloadLoading ...