Identifying the mechanisms behind loss of muscle function in non-small cell lung cancer patients

• Grant number: 19/17009-7
• Support Opportunities: Scholarships abroad - Research Internship - Doctorate
• Start date: February 01, 2021
• End date: January 31, 2022
• Field of knowledge: Health Sciences - Medicine
• Principal Investigator: Gilberto de Castro Junior
• Grantee: Willian das Neves Silva
• Supervisor: Kathryn J. Swoboda
• Host Institution: Instituto do Câncer do Estado de São Paulo Octavio Frias de Oliveira (ICESP). Coordenadoria de Serviços de Saúde (CSS). Secretaria da Saúde (São Paulo - Estado). São Paulo , SP, Brazil
• Institution abroad: Harvard University, Boston, United States
• Associated to the scholarship: 16/20187-6 - Caquexia in non-small cell lung cancer patient: physical fitness influence on prognosis, BP.DR

Abstract

Non-small-cell lung cancer (NSCLC) is the most common type of lung cancer and the leading cause of cancer-related deaths worldwide. Patients are frequently diagnosed in advanced stages and about half of all NSCLC patients present cancer cachexia, a syndrome characterized by skeletal muscle wasting, lower response to anticancer treatments and poor prognosis. Preliminary Data: We set to determine the relevance of testing skeletal muscle function as a predictor of prognosis in NSCLC patients. We have included 26 patients in this study, performing physical functional tests, muscle biopsy and blood samples drawn. Preliminary results indicate that patients with impaired muscle function display lower survival rate than patients with better muscle function. Thus, identifying the mechanisms underlying the impaired muscle function is critical to develop new treatments for NSCLC patients. Aim: To identify 1) whether circulating factors from cachectic patients induce functional changes in human myotubes in vitro and 2) the main affected signaling pathways in these treated myotubes. Methods: To address the first topic, we have collected serum from all studied patients. Healthy human myotubes will be incubated with different concentrations of NSCLC patients' serum. We will evaluate multiple functional endpoints in the myotubes, including ATP production rate, oxygen consumption rate, extracellular acidification rate, myotube diameter and markers of muscle atrophy. Moreover, in 3D engineered myotubes, we will evaluate contractile properties. To address the second topic, we will perform an unbiased transcriptome analysis for the treated myotubes followed by pathways analysis. To further validate these findings in vivo, we will use muscle biopsies collected from these NSCLC patients. Perspectives: A broad investigation (functional evaluation, circulating biomarkers and gene expression) will permit to identify those alterations in cachectic NSCLC patients that can be of both prognostic and predictive relevance (targetable) in this scenario. We also have as a perspective, to identify novel circulating factors responsible for the loss of muscle function in these patients using proteomic approaches. (AU)