Analysis of the efficacy of L-asparaginase in inhibiting the metastatic process in a human Melanoma cell line

• Grant number: 22/02076-3
• Support Opportunities: Scholarships in Brazil - Doctorate (Direct)
• Start date: May 01, 2023
• End date: January 31, 2026
• Field of knowledge: Biological Sciences - Pharmacology - Biochemical and Molecular Pharmacology
• Principal Investigator: Gisele Monteiro
• Grantee: Carolina Silva
• Host Institution: Faculdade de Ciências Farmacêuticas (FCF). Universidade de São Paulo (USP). São Paulo , SP, Brazil

Abstract

Melanoma is an aggressive skin neoplasm with high plasticity, drug resistance and a propensity to metastasize. 50% of patients with this disease have a mutation in the BRAF protein kinase, which results in exacerbated activation of the MAPK pathway. Patients with this mutation are eligible to be treated with MAPK inhibitors, but may exhibit drug resistance and increased tumor invasiveness in response. Recently, restriction of L-asparagine (Asn) has been shown to have pharmacological potential in the treatment of solid tumors prone to metastases. An efficient approach to the depletion of this amino acid is treatment with the enzyme L-asparaginase (ASNase). Recent data from the literature show that the inclusion of ASNase in the treatment of solid tumors reduces the formation of metastasis. Thus, the objective of this work is to evaluate the effect of ASNase and combinatorial treatment of ASNase and MAPK pathway inhibitor in the metastatic process in BRAF human melanoma. Previously, in vitro assays were performed to determine the effect of treatment with ASNase and/or BRAF inhibitor on the metabolic viability and colony formation capacity of melanoma cell lines. In this direct doctoral project, in vitro tests are planned to evaluate the effect of these treatments on the processes of cell migration and invasion, as well as in vivo tests to analyze possible changes in metastatic capacity, formation of circulating tumor cells and in molecular mechanisms. (AU)