Effects of combined aerobic and resistance training on the response to chemotherapy in patients with metastatic colorectal cancer: contribution of miRNAs

• Grant number: 24/03531-1
• Support Opportunities: Regular Research Grants
• Start date: October 01, 2024
• End date: September 30, 2026
• Field of knowledge: Health Sciences - Physical Education
• Principal Investigator: Telma Fátima da Cunha Moraes
• Grantee: Telma Fátima da Cunha Moraes
• Host Institution: Instituto de Ciências da Saúde (ICS). Universidade Paulista (UNIP). São Paulo , SP, Brazil
• Associated researchers: Carlos Ugrinowitsch ; Cláudia Lúcia de Moraes Forjaz ; Patricia Chakur Brum ; Tiago Fernandes

Abstract

Colorectal cancer is the third most common type of cancer in the world. About 25% of patients have metastasis (stage IV) at diagnosis and about 50% will eventually develop metastatic disease, which is the leading cause of death for most patients with this type of cancer. Although the presence of metastasis reduces the chances of cure, an increase in the survival of patients with metastasis has been observed in the last two decades, reaching about 30 months in clinical trials. This increase in survival can be attributed to new therapeutic approaches that attack specific targets of the tumor and/or its microenvironment. However, both the disease and the treatment can produce symptoms and signs such as weight loss, fatigue, pain, loss of appetite and peripheral neuropathy, which impair the quality of life of these patients. Thus, strategies or interventions that can attenuate or reverse these symptoms and signs, increase survival, improve quality of life and even control tumor development and metastases, are crucial in the process of treating patients with metastatic colorectal cancer. Among the strategies, exercise training and, in particular, combined aerobic and resistance training, has been shown to be effective not only for prevention, but as an adjuvant in cancer treatment, contributing to increased survival, reduced fatigue and improved quality of life. A mechanism related to these responses concerns the ability of skeletal muscle to produce and release molecules, the myokines, during and immediately after physical exercise, stimulating internal signaling and/or communication with other organs and tissues, such as the liver, the adipose tissue and the heart. Among the myokines, microRNAs (miRNAs) have been highlighted. They are carried by extracellular vesicles and can produce several local and distant antineoplastic effects, as observed, for example, in breast cancer. However, there are no reports whether miRNAs can minimize the genesis and progression of metastatic colorectal cancer. In addition, little is known about the relationship of these molecules with the improvement of physical fitness, treatment tolerance and quality of life and, consequently, reduction of toxicity and metastasis progression in these patients. In this sense, this proposal will consist of a cross-sectional study and a longitudinal study to evaluate patients with metastatic colorectal cancer. The cross-sectional study will verify whether there is an association between the level of physical activity and tumor progression before starting chemotherapy. The longitudinal study will assess whether the production of miRNAs, present in extracellular vesicles, in patients undergoing combined aerobic and resistance training for 12 weeks, is associated with an improved response to chemotherapy. We will also verify the effect of combined exercise training on physical fitness, physical activity level, body composition, treatment tolerability and toxicity, immune system parameters, symptoms and quality of life. Our hypotheses are: 1) a higher level of physical activity will be associated with a lower tumor progression before chemotherapy treatment; 2) the miRNAs produced by combined aerobic and resistance training associated with chemotherapy may favor a better response to treatment and clinical and functional parameters when compared to chemotherapy alone. (AU)