Overcoming Resistance to Anabolic Selective Androgen Receptor Modulator (SARM) Therapy in Experimental Cancer Cachexia with Histone Deacetylase Inhibitor AR-42

Abstract

BackgroundCancer cachexia impacts the majority of advanced cancer patients but no approved anticachexia therapeutic exits. Recent late stage clinical failures of anabolic anti-cachexia therapy revealed heterogeneous responses to anabolic therapies and a limited ability to translate improved body composition into functional benefit. It is currently unclear what governs anabolic responsiveness in cachectic patient populations. Methods We evaluated anabolic androgen therapy combined with the novel anti-cachectic histone deacetylase inhibitor (HDACi) AR-42 in a series of studies using the C-26 mouse model of experimental cachexia. The ability of treatment to suppress tumor-mediated catabolic signaling and promote anabolic effects were characterized. Results Anabolic anti-cachexia monotherapy with the selective androgen receptor modulator (SARM) GTx-024 or enobosarm had no impact on cachectic outcomes in the C-26 model. A minimally effective dose of AR-42 provided mixed anti-cachectic benefits when administered alone but when combined with GTx-024 significantly improved bodyweight (p <0.0001), hind limb muscle mass (p <0.05), and voluntary grip strength (p <0.0001) versus tumor bearing controls. Similar efficacy resulted from the combination of AR-42 with multiple androgens. Anti-cachectic efficacy was associated with the ability to reverse pSTAT3 and atrogene induction in gastrocnemius muscle of tumor-bearing animals in the absence of treatment-mediated changes in serum IL-6 or LIF. Conclusions Anabolic GTx-024 monotherapy is incapable of overcoming catabolic signaling in the C-26 model of experimental cachexia. Anti-cachectic androgen therapy is greatly improved by successful blockade of STAT3 mediated atrophy with AR-42. Combined androgen and HDAC inhibitor administration represents promising approach to improve anabolic response in cachectic patient populations.

Contribution of STAT3 to Inflammatory and Fibrotic Diseases and Prospects for its Targeting for Treatment

“…For example, there are reports that the histone deacetylase (HDAC) inhibitor, AR-42, is a potent inhibitor of STAT3 activity [49]. Recent experiments in the C26 cachexia mouse model using anabolic androgen therapy in combination with HDAC inhibitor AR-42 was shown to block STAT3 mediated muscle atrophy [163]. Ruxolitinib, a Jak1/2 inhibitor has also been found to result in a significant increase in body weight, in a phase II trial, in exocrinemetastatic pancreatic cancer patients [50,51].…”

Dual inhibitors of histone deacetylases and other cancer-related targets: A pharmacological perspective

“…In the anti-proliferation assay against LNCaP cells, compound 68 shows greater activity than apalutamide (ARN-509) [209]. The dual AR-HDACs inhibitor might have potential treatment benefit for anti-cachectic therapy [210] or castration-resistant prostate cancer [211]. <insert Table 19>…”