Friday, May 3, 2024
5/3/2024
PROJECT SUMMARY/ABSTRACT A decrease in muscle mass and function, known as sarcopenia, is highly prevalent in cancer patients and often leads to decreased endurance, increased fatigue, falls, poor quality of life (QOL) and increased mortality. Prostate cancer (PCa) is the 2nd most common cancer and the 2nd leading cause of cancer death in men worldwide, greatly impacting survival and QOL in these patients. Androgen deprivation therapy (ADT) is the standard treatment for advanced and metastatic PCa. Unfortunately, ADT exacerbates sarcopenia contributing to the symptom burden and poor overall QOL. Despite its relevance, there are no approved pharmacological treatments for sarcopenia. Several gaps in our knowledge impede the development of therapies for sarcopenia: 1) There is no agreement on the specific tools to assess clinically relevant outcomes, 2) The underlying mechanisms are not fully understood, 3) the lived experiences of these men have not been ascertained, and 4) we are currently unable to predict who will develop sarcopenia upon starting ADT. The Overall Goals of this proposal are to establish clinical outcomes and predictors of sarcopenia in PCa patients undergoing ADT, and to characterize pathways and mechanisms leading to this phenotype, including the role of mitochondria. We propose to perform a clinical trial including 70 men with a diagnosis of PCa starting ADT. Participants will be followed for 12 months. Changes in body composition, muscle strength, physical performance, and patient reported outcomes (PROs) including fatigue and QOL will be measured, and their clinical relevance ascertained. Blood samples and muscle biopsies will be obtained at baseline, 6 months, and 12 months to investigate genes, proteins, and metabolites altered by ADT and to establish the predictive value of these biomarkers on clinical outcomes of sarcopenia using a comprehensive multi-omics approach. The Specific Aims are to: 1) Establish the clinical relevance of different outcome measures to assess sarcopenia in PCa patients starting ADT. We hypothesize that ADT will cause clinically meaningful decreases in appendicular lean body mass (aLBM), muscle strength, physical performance and QOL, 2) Identify and prioritize the molecular pathways mediating the effects of ADT on these outcomes using a multi-omics approach. Our hypothesis is that ADT will alter gene expression, protein and metabolite levels in muscle and plasma as measured by a comprehensive multi-omics approach, and this will be associated with sarcopenia, 3) Determine the role of baseline biomarker levels as predictors of sarcopenia; 4) Perform mechanistic studies in muscle tissue to define the role of mitochondrial dysfunction in ADT-induced sarcopenia. We anticipate that specific pathways probed in plasma and muscle, and impairments in mitochondrial function at baseline will predict the development of sarcopenia upon starting ADT. We will also characterize the experience of these men with regard to impact on QOL. The data generated will provide essential knowledge on informative tools to measure clinically relevant outcomes in ADT-induced sarcopenia, and identify novel targets and clinically meaningful predictive biomarkers for this morbid condition.
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