ActRII blockade protects mice from cancer cachexia and prolongs survival in the presence of anti-cancer treatments

Abstract

Background: Cachexia affects the majority of patients with advanced cancer and is associated with reduced treatment tolerance, response to therapy, quality of life, and life expectancy. Cachectic patients with advanced cancer often receive anti-cancer therapies against their specific cancer type as a standard of care, and whether specific ActRII inhibition is efficacious when combined with anti-cancer agents has not been elucidated yet.

Methods: In this study, we evaluated interactions between ActRII blockade and anti-cancer agents in CT-26 mouse colon cancer-induced cachexia model. CDD866 (murinized version of bimagrumab) is a neutralizing antibody against the activin receptor type II (ActRII) preventing binding of ligands such as myostatin and activin A, which are involved in cancer cachexia. CDD866 was evaluated in association with cisplatin as a standard cytotoxic agent or with everolimus, a molecular-targeted agent against mammalian target of rapamycin (mTOR). In the early studies, the treatment effect on cachexia was investigated, and in the additional studies, the treatment effect on progression of cancer and the associated cachexia was evaluated using body weight loss or tumor volume as interruption criteria.

Results: Cisplatin accelerated body weight loss and tended to exacerbate skeletal muscle loss in cachectic animals, likely due to some toxicity of this anti-cancer agent. Administration of CDD866 alone or in combination with cisplatin protected from skeletal muscle weight loss compared to animals receiving only cisplatin, corroborating that ActRII inhibition remains fully efficacious under cisplatin treatment. In contrast, everolimus treatment alone significantly protected the tumor-bearing mice against skeletal muscle weight loss caused by CT-26 tumor. CDD866 not only remains efficacious in the presence of everolimus but also showed a non-significant trend for an additive effect on reversing skeletal muscle weight loss. Importantly, both combination therapies slowed down time-to-progression.

Conclusions: Anti-ActRII blockade is an effective intervention against cancer cachexia providing benefit even in the presence of anti-cancer therapies. Co-treatment comprising chemotherapies and ActRII inhibitors might constitute a promising new approach to alleviate chemotherapy- and cancer-related wasting conditions and extend survival rates in cachectic cancer patients.

Keywords: ActRII blockade; Cancer cachexia; Cisplatin; Combination; Everolimus.

Fig. 1

Effects of cisplatin and CDD866 on body weight. Non-tumor (a), CT-26 tumor (b), and body weight on day 10 (c). Values are expressed as means ± SEM (n = 7–8). Percent changes of body weight were calculated in comparison to treatment start. ^* P < 0.05, ^** P < 0.01 versus non-tumor control; ⁺⁺ P < 0.01 versus non-tumor cisplatin; ^& P < 0.05 versus CT-26 control; ^## P < 0.01 versus CT-26 cisplatin

Fig. 2

Effects of cisplatin and CDD866 on tumor. Tumor volume (a) and tumor weight (b). Values are expressed as means ± SEM (n = 6–8). ^&& P < 0.01 versus CT-26 control; ^## P < 0.01 versus CT-26 cisplatin; ^$$ P < 0.01 versus CT-26 CDD866

Fig. 3

Effects of cisplatin and CDD866 on muscle weight. Tibialis (a), gastrocnemius complex (b), and quadriceps (c). Values are expressed as means ± SEM (n = 6–8). Percent changes of muscle weight, normalized to initial body weight, were calculated in comparison to non-tumor control. ^* P < 0.05, ^** P < 0.01 versus non-tumor control; ⁺ P < 0.05, ⁺⁺ P < 0.01 versus non-tumor cisplatin; ^## P < 0.01 versus CT-26 cisplatin

Fig. 4

Effects of cisplatin and CDD866 on time-to-progression. Time-to-progression expressed by percentage of event defined by interruption criteria (a); median days elapsed before reaching an interruption criterion (b), expressed by box and whiskers with min to max; ^&& P < 0.01 versus CT-26 control; ^## P < 0.01 versus CT-26 cisplatin. Distribution by termination criterion (c) and breakdown of time-to-progression by body weight loss (d) and tumor volume (e)

Fig. 5

Effects of everolimus and CDD866 on body weight. Non-tumor (a), CT-26 tumor (b), and body weight on day 14 (c). Values are expressed as means ± SEM (n = 8–10). Percent changes of body weight were calculated in comparison to treatment start. ^** P < 0.01 versus non-tumor control; ⁺⁺ P < 0.01 versus non-tumor everolimus; ^&& P < 0.01 versus CT-26 control; ^## P < 0.01 versus CT-26 everolimus

Fig. 6

Effects of everolimus and CDD866 on tumor. Tumor volume (a) and tumor weight (b). Values are expressed as means ± SEM (n = 10). ^&& P < 0.01 versus CT-26 control; ^##:P < 0.01 versus CT-26 everolimus; ^$$: P < 0.01 versus CT-26 CDD866

Fig. 7

Effects of everolimus and CDD866 on muscle weight. Tibialis (a), gastrocnemius complex (b), and quadriceps (c). Values are expressed as means ± SEM (n = 10). Percent changes of muscle weight, normalized to initial body weight, were calculated in comparison to non-tumor control. ^** P < 0.01 versus non-tumor control; ⁺⁺ P < 0.01 versus Non-tumor everolimus; ^&& P < 0.01 versus CT-26 control; ^# P < 0.05 versus CT-26 everolimus

Fig. 8

Effects of everolimus and CDD866 on time-to-progression. Time-to-progression expressed by percentage of event defined by interruption criteria (a); median days elapsed before reaching an interruption criterion (b), expressed by box and whiskers with min to max; ^& P < 0.05, ^&& P < 0.01 versus CT-26 control; ^$ P < 0.05 versus CT-26 CDD866. Distribution by termination criterion (c) and breakdown of time-to-progression by body weight loss (d) and tumor volume (e)

Fig. 9

Effects of everolimus and CDD866 on phosphorylation of SMAD3 levels. Western blot image (a) and quantified value (b). Differentiated C2C12 cells stimulated with or without myostatin (Mst) were used as a positive control for detection of phosphorylation of SMAD3 levels. The lower, weaker band represents phosphorylated SMAD3. Values are expressed as means ± SEM (n = 5–10); **P < 0.01 versus non-tumor control; ^& P < 0.05, ^&& P < 0.01 versus CT-26 control; ^## P < 0.01 versus CT-26 everolimus

Fig. 10

Effects of everolimus and CDD866 on phosphorylation of mTOR levels. Total mTOR (a) and phospho-mTOR (b). Animals received their last injection of CDD866 on day 13 and were euthanized on day 14. Values are expressed as means ± SEM (n = 5–10); ^** P < 0.01 versus non-tumor control; ⁺⁺ P < 0.01 versus non-tumor everolimus; ^xx P < 0.01 versus non-tumor CDD866; ^&& P < 0.01 versus CT-26 control; ^## P < 0.01 versus CT-26 everolimus; ^$$ P < 0.01 versus CT-26 CDD866

Fig. 11

Effects of everolimus and CDD866 on inflammation and atrophy markers. IL-6 (a), MAFbx (b), and MuRF1 (c) levels. Animals received their last injection of CDD866 on day 13 and were euthanized on day 14. Values are expressed as means ± SEM; ^* P < 0.05, ^** P < 0.01 versus non-tumor control; ^& P < 0.05, ^&& P < 0.01 versus CT-26 control; ^## P < 0.01 versus CT-26 everolimus; ^$$ P < 0.01 versus CT-26 CDD866