Heterogeneity of oncogenic signaling associated with colon cancer metastases resistant to systemic therapy: Investigation by proteogenomics and modeling of complex networks

• Grant number: 19/20414-0
• Support Opportunities: Regular Research Grants
• Duration: April 01, 2021 - March 31, 2023
• Field of knowledge: Health Sciences - Medicine
• Principal Investigator: Fabio Albuquerque Marchi
• Grantee: Fabio Albuquerque Marchi
• Host Institution: A C Camargo Cancer Center. Fundação Antonio Prudente (FAP). São Paulo , SP, Brazil
• Associated researchers: Adriana Franco Paes Leme ; Ariane Fidelis Busso Lopes ; Celso Abdon Lopes de Mello ; David Corrêa Martins Junior ; Mariana Bisarro dos Reis ; Marina De Brot Andrade ; Paula Nicole Vieira Pinto Barbosa ; Rui Manuel Vieira Reis ; Silvia Regina Rogatto

Abstract

Colon cancer is a leading cause of cancer death worldwide. Although the survival of patients with metastatic disease has improved with the use of systemic therapy, many of them develop primary resistance with progression within a few months. Despite the genomic characterization of these tumors has positively influenced the therapy offered, it is still a challenge to identify alterations that impact the survival of tumor cells in patients with resistant metastatic disease. We hypothesized that specific driver alterations in these tumors modulate the oncogenic signaling dynamics leading to deregulation of pathway activity and acquisition of a resistance profile. Thus, this project proposes the search for these alterations in samples of colon cancer liver metastases resistant to systemic therapy using as a strategy a multidimensional molecular investigation approach of each evaluated sample. The main methodological steps include (1) computational modeling of signaling pathways and complex networks inference, (2) proteogenomic screening (mutational events, transcript level and proteomics) of 30 samples, 15 from patients with liver metastases with progression to the first line of therapy less than 3 months and 15 non-tumor paired samples, (3) data integration to uncover drivers involved with compensatory pathway activation and modification in oncogenic signaling behavior and (4) validation using tissue-microarray in a set of 300 samples for statistical association with clinical-pathological data and monitoring of mutational status using ctDNAs collected from 15 patients in 6 periods during treatment. We expect that this study has the potential to impact the precise detection of targets that are involved with mechanisms of resistance to therapy in metastases and contribute with innovative data that allow advances in the therapeutic strategies offered to patients. (AU)