Myokine Signaling Blockade Prevents Androgen Deprivation Therapy Induced Sarcopenia and Suppresses Tumor Growth
Authors: Pan Chunliu , Singh Shalini , Krolewski John , Nastiuk Kent 
Published: November 2023

The mainstay treatment of recurrent or metastatic prostate cancers is androgen deprivation therapy (ADT). These advanced cancers progress relatively slowly, and patients often receive ADT for years, meaning that any side effects of ADT can have a significant impact on the health of the prostate cancer patients. One of The mainstay treatment of recurrent or metastatic prostate cancers is androgen deprivation therapy (ADT). These advanced cancers progress relatively slowly, and patients often receive ADT for years, meaning that any side effects of ADT can have a significant impact on the health of the prostate cancer patients. One of the most frequent side effects, possibly afflicting as many as 200,000 patients, is progressive loss of muscle mass (sarcopenia), typically accompanied by functional deficits in these patients. Exercise therapy has shown promise as a potential treatment for ADT‐induced sarcopenia, but has not been found to reverse the functional deficits, indicating it is urgent to improve this therapy or develop additional or complementary therapies. We have previously investigated ADT‐induced sarcopenia in a non‐tumor bearing mouse model. The castration‐induced changes closely resembled the loss of skeletal muscle strength and body composition that occurs in ADT treated patients. ActRIIB‐Fc (Acceleron's investigational ‘tool’ drug RAP‐031), which binds and blocks multiple myokines, inhibited sarcopenia in our normal mouse model. We examined the expression of TGFß family members that bind RAP‐031 in our model and found that muscle levels of myostatin (by immunoblot), activins A, AB, B and GDF11 (all by ELISA performed on muscle extracts) all increase over time, but with distinctive kinetics. Here we used castrated PBCre4 × PTENf/f tumor‐bearing mice and measured tumor volume (by ultrasound and 3D‐image reconstruction), body composition (by NMR), muscle mass, fat mass (by micro‐CT), grip strength and expression of TGFß family members. ADT of PTEN‐deficient tumor‐bearing mice reduces muscle mass, overall lean body mass (LBM), increases fat and reduces grip strength, similar to non‐tumor bearing mice. RAP‐031 treatment of castrated PTEN‐deficient mice reversed these phenotypic changes that resemble ADT side effects in human patients. Surprisingly, myokine inhibition also induces prostate tumor regression in the absence of ADT, and increased the rate and degree of castration induced prostate tumor regression in this model. These results suggests that myokines might be both biomarkers and potential targets for therapy to reduce this co‐morbidity in prostate cancer patients and may also control tumor growth directly.Support or Funding InformationThis work was supported by a New York State Prostate Cancer Research Program Award C030321 and grant HHS‐6‐15SF from the S.A.S. Foundation (K.L.N), and National Cancer Institute grant CA151753 (J.J.K.) and P30AR061307 and P30CA016056. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.