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• W3190056898 abstract "You have accessJournal of UrologyKidney Cancer: Basic Research & Pathophysiology II (PD49)1 Sep 2021PD49-11 COMBINING NEDDYLATION INHIBITION WITH CHEMOTHERAPY TO TREAT RENAL MEDULLARY CARCINOMA Daniel Shapiro, Niki Millward Zacharias, Durga Tripathi, Jean-Philippe Bertocchio, Melinda Soeung, Priya Rao, Cheryl Walker, Giannicola Genovese, Nizar Tannir, Christopher Wood, Jose Karam, and Pavlos Msaouel Daniel ShapiroDaniel Shapiro More articles by this author , Niki Millward ZachariasNiki Millward Zacharias More articles by this author , Durga TripathiDurga Tripathi More articles by this author , Jean-Philippe BertocchioJean-Philippe Bertocchio More articles by this author , Melinda SoeungMelinda Soeung More articles by this author , Priya RaoPriya Rao More articles by this author , Cheryl WalkerCheryl Walker More articles by this author , Giannicola GenoveseGiannicola Genovese More articles by this author , Nizar TannirNizar Tannir More articles by this author , Christopher WoodChristopher Wood More articles by this author , Jose KaramJose Karam More articles by this author , and Pavlos MsaouelPavlos Msaouel More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000002071.11AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Renal medullary carcinoma (RMC) is a rare and aggressive malignancy that primarily affects young patients of African descent with sickle cell trait. No targeted therapies are currently approved for patients with RMC. The current standard of care consists of platinum-based chemotherapy and new therapies are needed. We previously identified proteotoxic and replication stress as RMC hallmarks. The neddylation pathway protects cells from proteotoxic and replication stress. We hypothesized that inhibition of neddylation will produce antitumor responses in RMC. METHODS: We tested the efficacy of neddylation activating enzyme inhibitor pevonedistat (MLN4924) in vitro in the platinum-naïve RMC2C and the platinum-experienced RMC219 cell lines, as well as in vivo in the platinum-naïve RMC2X and the platinum-experienced RMC32X patient-derived xenograft (PDX) models. Cell viability was evaluated using MTT assays. To determine the effects of pevonedistat in combination with platinum-based cytotoxic chemotherapy (carboplatin+paclitaxel) in vivo, immunodeficient mice bearing subcutaneous RMC tumors were divided into 4 treatment arms (n=5-8 per arm) which consisted of vehicle control, pevonedistat (30mg/kg), carboplatin (80mg/kg)+paclitaxel (20mg/kg), and pevonedistat+carboplatin+paclitaxel. Synergy between pevonedistat and chemotherapy was determined based on the Bliss definition of drug independence. RESULTS: Pevonedistat showed in vitro antitumor efficacy against both RMC2C (IC50 0.199 μΜ) and RMC219 (IC50 0.551) cell lines. In the RMC2X in vivo model, mean tumor volumes were 2164±835mm3 for control, 433±250mm3 for pevonedistat, 339±44mm3 for chemotherapy, 75±46mm3 for pevonedistat+chemotherapy. The combination of pevonedistat with chemotherapy significantly reduced tumor volumes compared to vehicle control (p=0.02) and chemotherapy alone (p=0.008). A similar pattern was demonstrated with RMC32X tumor volumes, whereby pevonedistat combined with chemotherapy significantly reduced tumor volume compared to control (p=0.006) and chemotherapy alone (p=0.02). A significant synergistic therapeutic effect of pevonedistat combined with chemotherapy was found for both RMC2X (p=0.008) and RMC32X (p=0.002). CONCLUSIONS: Our results identify the neddylation pathway as a targetable vulnerability of RMC tumors, and provide preclinical rationale for a clinical trial testing the combination of pevonedistat with carboplatin+paclitaxel to improve the RMC outcomes. Source of Funding: Supported in part by the Cancer Center Support Grant to MDACC (grant P30CA016672) from the National Cancer Institute of the National Institutes of Health and by a Concept award (W81XWH1810570) from the United States Department of Defense © 2021 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 206Issue Supplement 3September 2021Page: e849-e849 Advertisement Copyright & Permissions© 2021 by American Urological Association Education and Research, Inc.MetricsAuthor Information Daniel Shapiro More articles by this author Niki Millward Zacharias More articles by this author Durga Tripathi More articles by this author Jean-Philippe Bertocchio More articles by this author Melinda Soeung More articles by this author Priya Rao More articles by this author Cheryl Walker More articles by this author Giannicola Genovese More articles by this author Nizar Tannir More articles by this author Christopher Wood More articles by this author Jose Karam More articles by this author Pavlos Msaouel More articles by this author Expand All Advertisement Loading ..." @default.
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• W3190056898 title "PD49-11 COMBINING NEDDYLATION INHIBITION WITH CHEMOTHERAPY TO TREAT RENAL MEDULLARY CARCINOMA" @default.
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