Effects of RAS/RAF signaling pathway inhibition in pediatric solid tumor cells

• Grant number: 24/13320-8
• Support Opportunities: Scholarships in Brazil - Scientific Initiation
• Start date: March 01, 2025
• End date: February 28, 2026
• Field of knowledge: Biological Sciences - Biology
• Principal Investigator: Mariana Camargo Maschietto
• Grantee: Bruna Vasconcelos Martins
• Host Institution: Centro Infantil de Investigações Hematológicas Dr Domingos A Boldrini (CIB). Campinas , SP, Brazil

Abstract

Pediatric cancer accounts for about 3% of the malignant tumors registered in the Brazilian Population-Based Cancer Registries, with an estimated 7900 new cases per year for 2023-2025. Pediatric cancer has a distinct biological profile from adult tumors, which are more prevalent and better studied. Omics studies have been characterizing the molecular alterations of pediatric tumors, potentially making individualized and precise treatments easier. About half of pediatric tumors have alterations that could be targeted by therapy, such as activating mutations in genes of the RAS/RAF signaling pathway. This pathway is involved in cell proliferation, survival, growth and differentiation, and mutations in its genes can lead to the development of neoplasms, as seen in gliomas, retinoblastoma and neuroblastomas. Our research group has established a protocol for culturing tumoroids derived from tumors implanted in patient-derived xenografts (PDX), enabling in vitro drug tests. Preliminary tests were conducted on two types of neuroblastoma tumoroids: one with an NRAS mutation and the other with no mutations in genes of the RAS/RAF pathway. Both were treated with selumetinib and trametinib, specific drugs to this pathway. In the mutated tumoroid, treatment led to cell death, while in the non-mutated tumoroid, the results were not as evident. Given these results, this project aims to test both drugs in other RAS/RAF-mutated pediatric tumoroids, to verify cell sensitivity and the antitumor effects of these drugs, considering the molecular alterations regardless of tumor type.