Effect of a soluble activin receptor type IIB on androgen-deprivation-induced effects on body composition

Abstract

5133 Background: Androgen deprivation therapy (ADT) is a well-established treatment for hormone sensitive prostate cancer, but is associated with adverse side effects including loss of bone and lean mass and increased adipose mass. Activin receptor type IIB (ActRIIB) signaling is necessary for the negative regulation of lean tissue mass and treatment with a non-signaling, decoy ActRIIB results in a robust increase in lean tissue mass. Methods: Similar to ADT patients, orchiectomized (ORX) mice lose bone and lean mass and gain fat mass. To determine the therapeutic potential of inhibiting ActRIIB signaling to reduce the negative effects associated with ADT, we treated sham-operated (SHAM) and orchiectomized (ORX) mice with RAP-031, a fusion protein comprised of a form of the extracellular domain of ActRIIB linked to a murine Fc. Mice received twice weekly injections for 10 weeks with either vehicle (VEH) or 10 mg/kg RAP-031 (RAP). NMR scanning was used to determine body composition and whole body DEXA scans were performed to determine bone mineral density (BMD). Results: ORX resulted in a 4.4% decrease in BMD, an 18% reduction in lean tissue and a 41.6% increase in adiposity compared to the VEH-SHAM cohort. Both RAP-031treated groups of mice had significantly increased BMD and lean tissue mass and decreased adipose mass compared to their respective VEH groups. However, BMD, lean tissue and adiposity were not significantly different between the VEH-SHAM and RAP-ORX groups. These data illustrate that RAP-031 treatment completely attenuates ORX-induced alterations in bone, lean and fat mass. Conclusions: These data support the hypothesis that treatment with a form of soluble ActRIIB can offset negative side effects of ADT and have significant therapeutic implications for the treatment of patients with prostate cancer. [Table: see text] [Table: see text]