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

Abstract

No approved therapy exists for cancer-associated cachexia. The colon-26 mouse model of cancer cachexia mimics recent late-stage clinical failures of anabolic anti-cachexia therapy and was unresponsive to anabolic doses of diverse androgens, including the selective androgen receptor modulator (SARM) GTx-024. The histone deacetylase inhibitor (HDACi) AR-42 exhibited anticachectic activity in this model. We explored combined SARM/AR-42 therapy as an improved anti-cachectic treatment paradigm. A reduced dose of AR-42 provided limited anti-cachectic benefits, but, in combination with GTx-024, significantly improved body weight, hindlimb muscle mass, and grip strength versus controls. AR-42 suppressed the IL-6/GP130/STAT3 signaling axis in muscle without impacting circulating cytokines. GTx-024-mediated bcatenin target gene regulation was apparent in cachectic mice only when combined with AR-42. Our data suggest cachectic signaling in this model involves catabolic signaling insensitive to anabolic GTx-024 therapy and a blockade of GTx-024-mediated anabolic signaling. AR-42 mitigates catabolic gene activation and restores anabolic responsiveness to GTx-024. Combining GTx-024, a clinically established anabolic therapy, with AR-42, a clinically evaluated HDACi, represents a promising approach to improve anabolic response in cachectic patients.

Murine cancer cachexia models replicate elevated catabolic pembrolizumab clearance in humans

“…Three independent experiments were performed for each model with a group size of n = 5, except for one C26 experiment, in which group size was n = 3. Cachexia was established and evaluated in both models in a manner similar to that previously described 31 . Briefly, C26 tumours were established in the right flanks of male CD2F1 mice by subcutaneous injection of 0.5 × 10 6 C26 cells in 0.1 mL of PBS.…”

“…Cachexia was established and evaluated in both models in a manner similar to that previously described. 31 Briefly, C26 tumours were established in the right flanks of male CD2F1 mice by subcutaneous injection of 0.5 × 10 6 C26 cells in 0.1 mL of PBS. LLC tumours were established in the right upper hind limbs of male C57BL/6 mice by intramuscular injection of 0.5 × 10 6 LLC cells in 0.05 mL of PBS.…”

“…Real-time quantitative PCR was performed, and data were analysed and presented as previously reported, using ACTB (β-actin) as a reference gene. 31 Primer pairs for analyses included FcRn, Fd: 5′-AGCT CAAGTTCCGATTCCTG-3′, Rd: 5′-GATCTGGCTGATGAATCTAGG TC-3′, and β-Actin, Fd: 5′-AAGATCAAGATCATTGCTCCTCCTG-3′, Rd: 5′-AAACGCAGCTCAGTAACAGTC-3′.…”

A new trend in use of performance enhancing drugs in CrossFit®

“…Dalšími souvisejícími efekty jsou zvýšení svalové síly nebo zlepšení ve funkčních testech (Zilbermint & Dobs, 2009). Pozitivní efekt na zvýšení síly potvrzují Liva et al (2020).…”

The differentiation of hematopoietic stem cells was reprogrammed in advanced tumor-bearing mice

“…As a fatal, polyfactorial, and irreversible syndrome, cachexia affects about 50-80% of patients with various types of tumors [3] . Cancer cachexia has been defined by an international consensus as a multifactorial syndrome including loss of weight, muscle atrophy, weakness, anorexia, fatigue, low immunity and severe hematopoietic abnormalities [4][5][6][7] . It is well accepted to concentrates on cachexia as a metabolic disorder.…”