Prevention of body weight loss and sarcopenia by a novel selective androgen receptor modulator in cancer cachexia models

Abstract

Abstract. Cancer cachexia is a syndrome that impairs the quality of life and overall survival of patients, and thus the effectiveness of anticancer agents. There are no effective therapies for cancer cachexia due to the complexity of the syndrome, and insufficient knowledge of its pathogenesis results in difficulty establishing appropriate animal models. Previously, promising results have been obtained in clinical trials using novel agents including the ghrelin receptor agonist anamorelin, and the selective androgen receptor modulator (SARM) enobosarm to treat cachexia in patients with cancer. The present study examined the pharmacological effects of SARM-2f, a novel non-steroidal small molecule SARM, in animal models. SARM-2f increased body and skeletal muscle weight without significantly increasing the weight of the seminal vesicles or prostates of the castrated male rats. In the mice with tumor necrosis factor α-induced cachexia, SARM-2f and TP restored body weight, carcass weight, and food consumption rate. In the C26 and G361 cancer cachexia animal models, body and carcass weight, lean body mass, and the weight of the levator ani muscle were increased by SARM-2f and TP treatments. Tissue selectivity of SARM-2f was also observed in these animal models. The results demonstrate the anabolic effects of SARM-2f in a cytokine-induced cachexia model and other cancer cachexia models, and suggest that SARM-2f may be a novel therapeutic option for cachexia in patients with cancer. IntroductionCancer cachexia is defined as a multifactorial disorder associated with an ongoing loss of skeletal muscle mass with or without loss of fat mass, which leads to a progressive functional impairment that cannot be fully reversed with conventional nutritional supplementation (1). The symptoms appear in up to 80% of patients with cancer and account for at least 20% of cancer-associated deaths (1,2). Cancer cachexia has been reported to be caused by nutritional deficiencies, metabolic disorders, and inflammatory disorders (3-6). Presently, however, there is no approved therapy for the treatment or prevention of cancer cachexia. Therefore, an effective therapy for cancer cachexia is an unmet medical need. There are several potential therapeutic approaches for cancer cachexia (7-10). Androgen is a steroid hormone with multiple physiological functions including promotion of growth hormone release, appetite stimulation, anabolic actions, stimulatory effects on the central nervous system (CNS), and regulation of energy homeostasis. Low plasma androgen levels are often observed in patients with terminal cancer (11,12). Therefore, androgen-based treatments might be a potential therapy for cancer cachexia. However, testosterone replacement therapy has unavoidable side effects such as myocardial infarction, heart failure, stroke, depression, and aggression (13,14).In a previous study, we reported the 4-(pyrrolidin-1-yl) benzonitrile derivative as a selective androgen receptor modulator (SARM)-1c (15). Unlike testosterone, SARM-1c exhibited an...

A selective androgen receptor modulator SARM‐2f activates androgen receptor, increases lean body mass, and suppresses blood lipid levels in cynomolgus monkeys

“…In this study, the effective dose to increase BW by approximately 10% in monkeys was 10 mg/kg, and the AUC 0‐24h at 10 mg/kg was 8152 ng·h/mL. A dose of 0.3 mg/kg is sufficient to increase BW in rats . These findings indicate that monkeys required an approximately 30‐fold higher drug exposure to gain BW, compared with rats.…”

“…We previously reported that SARM‐2f increased skeletal muscle weight with a much lesser effect on prostate weight . The mechanisms for tissue selectivity of SARM includes two factors: recruitment of specific cofactors to AR and a tissue‐specific cofactor expression profile .…”

“…We previously reported that SARM-2f increased skeletal muscle weight with a much lesser effect on prostate weight. [15][16][17] The mechanisms for tissue selectivity of SARM includes two factors: recruitment of specific cofactors to AR and a tissue-specific cofactor expression profile. 26,27 We reported that SARM-2f induced less recruitment of the protein inhibitors of the activated STATs family to the AR than did testosterone.…”

“…Selective androgen receptor modulator (SARM) compounds, such as ostarine, significantly increased body weight, muscle mass, and muscle strength in preclinical rodent studies, and increased muscle mass in clinical trials . Our non‐steroidal small molecule, SARM compound, SARM‐2f (4′‐[(2S,3S)‐2‐Ethyl‐3‐hydroxy‐5‐oxopyrrolidin‐1‐yl]‐2′‐(trifluoromethyl) benzonitrile), also increases muscle weight and stimulates motor activity, food intake, and sexual behavior in rodent models . Currently, there are only a few reports showing the pharmacological effect of SARM compounds in monkeys: effects on blood high‐density lipoprotein cholesterol (HDL‐c) and overall gene expression profiles in the muscle .…”

“…14 Our non-steroidal small molecule, SARM compound, SARM-2f (4′-[(2S,3S)-2-Ethyl-3-hydroxy-5-oxopyrrolidin-1-yl]-2′-(trifluoromethyl) benzonitrile), also increases muscle weight and stimulates motor activity, food intake, and sexual behavior in rodent models. [15][16][17] Currently, there are only a few reports showing the pharmacological effect of SARM compounds in monkeys: effects on blood high-density lipoprotein cholesterol (HDL-c) 18 and overall gene expression profiles in the muscle. 19 In this study, we investigated the pharmacological effects of SARM-2f in cynomolgus monkeys in vitro and in vivo.…”