Overcoming resistance to anabolic SARM therapy in experimental cancer cachexia with an HDAC inhibitor

Area of Science:

• Oncology
• Pharmacology
• Muscle Physiology

Background:

• Cancer-associated cachexia lacks effective treatments, with recent anabolic therapies failing in late-stage clinical trials.
• The colon-26 mouse model reflects these clinical failures, showing unresponsiveness to anabolic androgens like GTx-024.
• Histone deacetylase inhibitor (HDACi) AR-42 demonstrated anti-cachectic effects in this model.

Purpose of the Study:

• To investigate the efficacy of a combined therapy using a selective androgen receptor modulator (SARM) GTx-024 and HDACi AR-42 for cancer cachexia.
• To determine if combining these agents could overcome the unresponsiveness observed with single-agent therapies.

Main Methods:

• Utilized the colon-26 mouse model of cancer cachexia.
• Administered reduced doses of AR-42 alone and in combination with GTx-024.
• Assessed body weight, hindlimb muscle mass, grip strength, and molecular signaling pathways (IL-6/GP130/STAT3, β-catenin).

Main Results:

• Combined GTx-024 and AR-42 therapy significantly improved body weight, muscle mass, and grip strength compared to controls.
• AR-42 suppressed the IL-6/GP130/STAT3 signaling axis in muscle tissue.
• GTx-024's anabolic effects on β-catenin target genes were only observed when combined with AR-42.

Conclusions:

• Cancer cachexia signaling involves anabolic resistance to therapies like GTx-024.
• AR-42 mitigates catabolic signaling and restores responsiveness to anabolic agents.
• Combination therapy of GTx-024 and AR-42 presents a promising strategy to enhance anabolic responses in cachectic patients.