Intramuscular Mechanisms of Androgen Deprivation-related Sarcopenia

Prostate cancer (PCa) is the most common cancer among men. Androgen deprivation therapy (ADT) is the standard treatment for advanced and metastatic PCa and nearly 400,000 men remain on androgen deprivation therapy (ADT) for advanced PCa in the U.S. Unfortunately, ADT also induces a decrease in muscle mass and function, known as sarcopenia, a condition that leads to decreased endurance, increased fatigue, falls, poor health-related quality of life (HR-QOL) and increased mortality. The mechanisms underlying the development of ADT-induced sarcopenia are incompletely understood and remain a significant barrier to the development of therapies for this condition. Mitochondria play an essential role in generating the adenosine triphosphate (ATP) needed for muscle contraction and abnormalities in mitochondria function have been reported in animal models of sarcopenia. The extent to which mitochondrial dysfunction mediates ADT-induced sarcopenia and muscle dysfunction is not known.

The overall goal of this proposal is to establish the role of mitochondrial dysfunction on ADT-induced sarcopenia in patients with PCa. The investigators hypothesize that ADT in men with PCa will induce mitochondrial dysfunction leading to sarcopenia.

Improving scientific understanding of the mechanisms underlying sarcopenia following ADT will enable investigators to develop new treatments and novel biomarkers for this disease. Given that there are no available therapies for sarcopenia, this is clinically very relevant. The near-term impact of this proposal will be to elucidate the extent to which mitochondrial dysfunction mediates the development of sarcopenia in veterans and non-veterans with prostate cancer undergoing ADT, and to evaluate the potential for these measurements at baseline to serve as early predictors of disease. The outcomes that will be directly attributed to the results of the proposed research include baseline and changes in muscle mass and performance, in-vivo and ex-vivo mitochondrial function, and patient reported outcomes (PROs) including fatigue and HR-QOL. The investigators expect that these efforts will have a major impact on the goal of reducing morbidity associated with prostate cancer, and improving HR-QOL by filling the gap in the knowledge of the mechanisms causing ADT-induced sarcopenia in PCa. The mechanisms identified in this grant will be the target of future interventional clinical trials.

The proposed project will address one of the PCRP overarching challenges and focus areas: "Survivorship including psychosocial impact on the patient". If the investigators prove the hypothesis that mitochondrial dysfunction plays a significant role in the development of sarcopenia, fatigue and poor HR-QOL in veterans and non-veterans with prostate cancer, the multidisciplinary team that has been assembled will build on these findings and test interventions currently undergoing clinical development to target mitochondria dysfunction in this population.

Inclusion criteria

• Histologically, cytologically, or image based documented advanced or metastatic PCa initiating ADT with expected continuous treatment for a minimum of 6 months and willing/able to provide informed consent.
• Willing and able to provide written informed consent prior to screening.

Exclusion criteria

• Liver disease (AST or ALT equal or more than 3x normal levels);
• Renal failure (creatinine equal or more than 2.5 mg/dL);
• Untreated thyroid disease, class III-IV CHF, AIDS;
• Other cancer diagnosed within the past five years other than non-melanoma skin cancer;
• Severe COPD requiring use of home O2;
• Chronic, uncontrolled hypertension as judged by the Investigator (i.e., Baseline SBP >150 mm Hg, DBP >90 mm Hg) or a SBP > 150 mm Hg or DBP > 95 mm Hg at the time of screening or baseline;
• An active, uncontrolled infection or cardiovascular disease including a recent myocardial infarction (MI), cerebrovascular accident (CVA), arrhythmias or unstable angina (< 6 months);
• Uncontrolled diabetes mellitus (as defined by a HbA1c equal or more than 9%);
• Underlying muscular or neuromuscular disorder or neurologic deficit contributing to sarcopenia;
• Enrolled in a clinical trial involving an investigational product or non-approved use of a drug/device or concurrently enrolled in medical research not scientifically or medically compatible with this study;
• Current use (within one month) of testosterone, high dose steroids (20mg of prednisone/day for more than 1 month), or megestrol treatment for cancer within the previous 3 months;
• Previous treatment with ADT other than oral anti-androgen at initiation of ADT;
• Metal implants in the right limbs (non-MRI compatible metal stents, titanium pins/markers, etc.) or implanted cardiac pacemaker or other implanted non-MRI compatible cardiac device (e.g., stent);
• A history of vascular problems (DVT, etc.)