Targeting the mTOR pathway through senotherapeutics to restore musculoskeletal health in cancer survivors

• Grant number: 24/20032-9
• Support Opportunities: Scholarships abroad - Research Internship - Post-doctor
• Start date: February 01, 2025
• End date: January 31, 2026
• Field of knowledge: Biological Sciences - Biochemistry - Molecular Biology
• Principal Investigator: Fernando Moreira Simabuco
• Grantee: Marcos Vinicius Esteca
• Supervisor: Lynda Faye Bonewald
• Host Institution: Escola Paulista de Medicina (EPM). Universidade Federal de São Paulo (UNIFESP). Campus São Paulo. São Paulo , SP, Brazil
• Institution abroad: Indiana University School of Medicine, United States
• Associated to the scholarship: 23/04275-6 - Lung Cancer-associated cachexia: the relationship between Parkin and mTOR pathways in the tumor and in skeletal muscle, BP.PD

Abstract

Colorectal cancer (CRC) is the third most common cancer diagnosed globally, and the number of survivors has been increasing significantly due to earlier diagnoses and advancements in treatment. Unfortunately, 50% of CRC patients that survive will develop debilitating musculoskeletal (MSK) deterioration, along with accelerated features of aging, such as increased frailty, morbidity, and mortality. We propose that acquiring an aging or senescence phenotype due to CRC and chemotherapy reduces the functionality of both bone and skeletal muscle, which is responsible for this accelerated MSK decline. Our hypothesis is that mTOR signaling and mitochondrial dysfunction are critical factors driving the senescence-associated phenotype in the MSK system of CRC survivors. In this project, we will assess the ability of serotherapeutic agents (Dasatinib, Quercetin, Zoledronate, Rapamycin) to improve MSK recovery after CRC resection and chemo cessation using morphological and functional assessments. We propose that senotherapeutics will improve recovery of the MSK system in CRC survivors by modulating the mTOR pathway. We will also validate whether specific inhibition of mTOR, using rapamycin, will have a comparable effect in terms of reducing senescence and improving MSK recovery. To investigate molecular mechanisms, in vitro experiments will be performed using co-cultures of cancer cells with bone and muscle cells with and without these senotherapeutic agents. These studies have the potential to lead to treatments for cancer survivors that will restore their health and physical activity to normal levels.