The primary goal of this research proposal is to understand the impact of chemotherapy on muscle mass and function, and to investigate whether muscle hypertrophy can protect against cancer cachexia and improve drug efficacy and patients'survival. It has been postulated that chemotherapy, among several other side effects, is also responsible for the development of cachexia. Cachexia, i.e. loss of body weight, muscle and fat mass, has currently no cure. The molecular mechanisms responsible for the development of this syndrome have been studied for some time, however little is known about the effects of various cancer treatments on cancer cachexia. On this line, it has been reported that several anticancer drugs can cause direct host cell modification as well as induce a negative nitrogen balance. However, the mechanism(s) regulating these processes deserve further attention. Our preliminary data and others'published findings support the idea that chemotherapy might promote muscle depletion. Indeed, chemotherapeutics such as cisplatin, irinotecan and gemcitabine, widely used in the treatment of different kinds of cancer, caused dose-dependent muscle fiber wasting in vitro and in vivo. Similarly, severe body weight loss and muscle atrophy were observed in mice bearing the Colon-26 and HCT- 116 colorectal cancers. Cancer patients affected by muscle depletion were more susceptible to severe chemotherapy-associated toxicity and showed reduced survival unlike subjects with larger muscle mass. Others and we showed that improving muscle mass in mice by pharmacological inhibition of the myostatin- family ligands, regulating muscle mass growth, rescued C26-cachexia and significantly prolonged survival. Altogether, these data suggest that cancer chemotherapy can promote the development of cachexia and that increasing muscle mass in the occurrence of a tumor might enhance drugs efficacy and safety, thus also prolonging survival. Our hypothesis will be explored by proposing the following aims: 1- Understand the impact of chemotherapy on muscle mass and function. Chemotherapy-associated direct toxicity on skeletal muscle and indirect production of atrophy-associated mediators will be tested in vitro and in vivo. Transcriptomic analysis will identify genes relevant for chemotherapy-induced muscle toxicity. Body composition, muscle functions (grip strength, ex-vivo contractility and fatigability), serum analyte profiling (cytokines, growth factors) and in vitro wasting activity will also be assessed. 2- Determine whether modulation of skeletal muscle mass affects chemotherapy response and tolerability. Mice bearing colorectal tumors (C26, HCT-116) will be receiving chemotherapy and/or ACVR2B/Fc, a peptide that promotes muscle growth. Effect on body composition and muscle functionality, as well as serum analyte profiling will be analyzed. Tumor growth and survival will also be evaluated.
The majority of patients diagnosed with cancer will receive chemotherapy and will show the symptoms of cachexia, a condition associated with loss of body weight and wasting of muscle and fat, and resulting in fatigue, poor quality of life, and often death. Using in vitro and mouse experimental models we will determine the mechanisms by which chemotherapy affects muscle mass and function and whether pharmacologically enhancing muscle mass can be protective against drug toxicity and prolong survival in cancer. This study will shed a light into the molecular pathways driving chemotherapy-associated cachexia and is required for the development of novel therapies aimed at increasing tolerability to chemotherapy and improving survival and quality of life in patients affected by cancer.
|Barreto, Rafael; Mandili, Giorgia; Witzmann, Frank A et al. (2016) Cancer and Chemotherapy Contribute to Muscle Loss by Activating Common Signaling Pathways. Front Physiol 7:472|
|Zimmers, Teresa A; Fishel, Melissa L; Bonetto, Andrea (2016) STAT3 in the systemic inflammation of cancer cachexia. Semin Cell Dev Biol 54:28-41|
|Barreto, Rafael; Waning, David L; Gao, Hongyu et al. (2016) Chemotherapy-related cachexia is associated with mitochondrial depletion and the activation of ERK1/2 and p38 MAPKs. Oncotarget 7:43442-43460|
|Bonetto, Andrea; Andersson, Daniel C; Waning, David L (2015) Assessment of muscle mass and strength in mice. Bonekey Rep 4:732|