Pharmacological targeting of the receptor for advanced glycation end-products (RAGE) to counteract cancer cachexia

Cachexia is a debilitating syndrome affecting more than 50% of advanced cancer patients and is directly responsible for about 20% of all cancer-associated deaths. Its major clinical feature is skeletal muscle atrophy leading to pronounced weight loss, reduced quality of life, and poor prognosis (1). Genetic ablation of RAGE (receptor for advanced glycation end-products) in tumor-bearing mice translates into reduced serum levels of cachexia-induced factors, delayed loss of muscle mass and strength, reduced tumor progression and increased survival. In cancer conditions, RAGE over-stimulated by high serum levels of its ligand, S100B, emerged as a determinant player in inducing cachexia, thus representing a promising target in therapeutic strategies (2). Here, we tested different pharmacological inhibitors (3,4) for their ability to reduce RAGE activity and counteract cancer cachexia. We treated Lewis lung carcinoma (LLC)-bearing C57Bl/6 mice with i.p. injections of the RAGE inhibitors, FPS-ZM1, Azeliragon (TTP488), RAP (RAGE antagonist peptide) and papaverine; and the S100B inhibitor, pentamidine, starting at the day of tumor appearance until 25 days post-tumor injection. We found that: i) Azeliragon and pentamidine showed toxic effects inducing death of mice before reaching the cachectic stage; ii) FPS-ZM1 and RAP did not counteract muscle wasting (in terms of weight loss and activation of the proteolytic systems); iii) papaverine reduced hallmarks of atrophy (body and muscle weight loss, protein degradation, and activation of the proteolytic systems) and prolonged survival. Thus, papaverine appears as the most efficacious pharmacological strategy targeting RAGE for anti-cachectic treatment, which is of great importance since an efficacious therapy for cachexia is still lacking. 1) Webster et al., Front Physiol. 2020; 2) Chiappalupi et al., J Cachexia Sarcopenia Muscle. 2020; 3) Singh & Agrawal, Drug Dev Res. 2022; 4) Saglam et al., J Neuroimmunol. 2021.