Abstract B092: Myokine signaling blockade prevents androgen deprivation therapy-induced sarcopenia and promotes prostate tumor regression

Abstract

One of the most significant side effects of androgen-deprivation therapy (ADT), the first-line therapy for recurrent and metastatic prostate cancer (PrCa), is sarcopenia (loss of skeletal muscle mass and function). ADT produces a significant disability syndrome in PrCa patients known as obese frailty. Use of ADT has been increasing such that side effects increasingly impact patient quality of life, and result in nursing home placement. The sarcopenia and functional loss of strength is recapitulated following castration of “middle-aged,” but not younger, male mice. In this model all five muscle-regulating TGFß superfamily members, known as myokines, are upregulated in distinctive temporal patterns during sarcopenia development. Complete myokine blockade fully restores muscle mass and strength in castrated mice. We castrated 6- to 9-month-old PbCre4 x PTENfl/fl PrCa-bearing mice and measured tumor volume (by high-frequency ultrasound), body composition (by NMR), muscle mass, fat mass, grip strength, and expression of TGFß family members. Tumor-bearing mice were treated with ActRIIB-Fc (or vehicle) to block myokine signaling; additional tumor-bearing mice were sacrificed biweekly to monitor myokine levels. In an autochthonous mouse model of PrCa, castration-induced changes closely resemble the loss of skeletal muscle strength and body composition that occurs in ADT treated patients. The reduction in muscle strength is comparable to that seen in patients. ADT reduces the mass of individual skeletal muscles, overall LBM, and grip strength. We examined the expression of myokines following castration and found that muscle levels of free dimeric myostatin, the activins, and GDF11 all increase over time, but with distinctive kinetics. Functionally, ActIIRB-Fc, which binds and blocks myokines, inhibits sarcopenia in our model, indicating that the myokines mediate ADT-induced sarcopenia. Surprisingly, this myokine inhibition also induced prostate tumor regression in the absence of ADT, suggesting a protumorigenic effect of myokines. Myokine inhibition also increased the rate of castration-induced prostate tumor regression in this model. In the tumor tissue and in the circulation, as in the muscle tissue of these mice, some of the myokines also increase post-castration. Myokines mediate the induction of sarcopenia following castration, and may also mediate tumor growth. These results suggest that myokines might be both biomarkers and potential targets for therapy to reduce this comorbidity in PrCa patients and may also control tumor growth directly. Citation Format: Chunliu Pan, Yanni Zulia, Kent L. Nasituk. Myokine signaling blockade prevents androgen deprivation therapy-induced sarcopenia and promotes prostate tumor regression [abstract]. In: Proceedings of the AACR Special Conference: Prostate Cancer: Advances in Basic, Translational, and Clinical Research; 2017 Dec 2-5; Orlando, Florida. Philadelphia (PA): AACR; Cancer Res 2018;78(16 Suppl):Abstract nr B092.