Abstract 3056: Growth differentiation factor 15 (GDF-15) inhibition attenuates platinum-based chemotherapy-induced emesis, anorexia and weight loss and increases survival

Abstract

Abstract Platinum-based chemotherapy is associated with nausea/emesis, anorexia and weight loss which reduce patient quality of life and limit treatment adherence potentially leading to poor treatment outcomes. Cisplatin increases circulating growth differentiation factor 15 (GDF-15), a cytokine that induces conditioned taste aversion, anorexia and weight loss in preclinical models. GDF-15 signals through the hindbrain receptor glial cell-derived neurotrophic factor receptor alpha-like (GFRAL). Cisplatin-induced anorexia/weight loss was attenuated in a GFRAL knockout mouse; therefore, we examined whether GDF-15 inhibition can prevent platinum-based chemotherapy-induced emesis, anorexia and weight loss, and also increase survival using mouse and/or nonhuman primate models. In cancer patients, platinum treatment increased circulating GDF-15 in non small cell lung carcinoma, colorectal, and ovarian cancer (~1.5 fold) compared to those receiving a non-platinum-based therapy. Furthermore, cisplatin, oxaliplatin and carboplatin administered individually all increased circulating GDF-15 in wildtype mice (≥ 5 fold) and induced anorexia, skeletal muscle wasting, and weight loss. GDF-15 mRNA was increased in kidney, liver, brain and white adipose tissue. These effects were prevented in GDF-15 knockout mice, however only a partial blockade was observed in the carboplatin group. In nonhuman primates, cisplatin treatment for 5 days (96% of the daily recommended clinical dose) also increased circulating GDF-15 (> 5 fold), and induced anorexia and emesis. Treatment with the anti-GDF-15 monoclonal antibody (mAB1) resulted in no detectable circulating levels of free GDF-15, and attenuated both cisplatin-induced anorexia and emesis. Furthermore, in a mouse cachectic tumor model (subcutaneous implantation of tumor tissue derived from human non-small cell lung carcinoma adenocarcinoma), cisplatin treatment inhibited tumor growth; however, GDF-15 levels were still elevated and additional weight loss occurred compared to vehicle control. When mAB1 was given in combination with cisplatin, weight loss was reversed and tumor growth inhibition was maintained, resulting in greater survival compared to cisplatin alone. Taken together, these data support the notion that GDF-15 inhibition with mAB1 holds the potential as an effective therapeutic approach to alleviate GDF-15 mediated emesis, anorexia and weight loss with the aim to enable optimal cancer treatment as well as to improve patient quality of life and potentially survival. Citation Format: Danna M. Breen, Kevin Beaumont, Donald Bennett, Julia Brosnan, Roberto Calle, Jeffrey R. Chabot, Susie Collins, Teresa Cunio, Ryan M. Esquejo, Stephanie Joaquim, Alison Joyce, Hanna Kim, Laura Lin, Betty Pettersen, Shuxi Qiao, Michelle Rossulek, Brendan Tierney, Karen M. Walters, Gregory Weber, Zhidan Wu, Bei B. Zhang, Morris J. Birnbaum. Growth differentiation factor 15 (GDF-15) inhibition attenuates platinum-based chemotherapy-induced emesis, anorexia and weight loss and increases survival [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 3056.