Abstract 1247: Targeting neddylation in combination with cytotoxic chemotherapy for the treatment of renal medullary carcinoma
Authors: Shapiro Daniel D. , Zacharias Niki Millward , Tripathi Durga N. , Bertocchio Jean-Philippe , Soeung Melinda , Rao Priya , Walker Cheryl L. , Genovese Giannicola , Tannir Nizar M. , Wood Christopher G. , Karam Jose A. , Msaouel Pavlos 
Published: July 2021

Abstract
Renal medullary carcinoma (RMC) is a rare and highly aggressive malignancy that affects primarily young patients of African descent with sickle cell trait. No targeted therapies are currently approved for patients with RMC and the median survival from diagnosis is only 13 months with the current standard of care therapy consisting of platinum-based cytotoxic chemotherapy. New therapeutic targets are urgently needed for this lethal disease. We previously identified proteotoxic and replication stress as hallmarks of RMC (Carugo et al. Cancer Cell, 2019; Msaouel et al. Cancer Cell, 2020). The neddylation pathway is a critical regulator that protects cells from proteotoxic and replication stress. We therefore hypothesized that inhibition of neddylation will produce antitumor responses in RMC. We accordingly tested the efficacy of the 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. Pevonedistat showed potent 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 again 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). Our results identify the neddylation pathway as a targetable vulnerability of RMC tumors, and provide in vitro and in vivo preclinical rationale for a clinical trial testing the combination of pevonedistat with carboplatin + paclitaxel to improve the outcomes of patients with this deadly malignancy.
Citation Format: Daniel D. Shapiro, Niki Millward Zacharias, Durga N. Tripathi, Jean-Philippe Bertocchio, Melinda Soeung, Priya Rao, Cheryl L. Walker, Giannicola Genovese, Nizar M. Tannir, Christopher G. Wood, Jose A. Karam, Pavlos Msaouel. Targeting neddylation in combination with cytotoxic chemotherapy for the treatment of renal medullary carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1247.