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Biomarkers of autophagy and fatty acid synthesis: tracking the response of melanoma spheroids to the drug holiday therapeutic regimen

Grant number: 20/12828-7
Support type:Scholarships in Brazil - Scientific Initiation
Effective date (Start): December 01, 2020
Effective date (End): November 30, 2021
Field of knowledge:Biological Sciences - Biochemistry - Enzymology
Principal researcher:Carmen Veríssima Ferreira
Grantee:Beatriz Aires Lopes
Home Institution: Instituto de Biologia (IB). Universidade Estadual de Campinas (UNICAMP). Campinas , SP, Brazil

Abstract

Melanoma is the most lethal type of skin cancer due to its high proliferative rate and capacity for metastasis. Additionally, this tumor displays low response to treatment, which in part is due to a high basal rate of autophagic flow. Therefore, the study of these cellular mechanisms and for the screening of compounds, the 3D culture models have been shown to be effective, as it allows greater similarity to the tumor in vivo, such as presenting zones (regions) with different gradients of nutrients, pH and oxygenation, and altered microenvironment. With this in mind, and based on the fact that violacein, a pigment derived from the secondary metabolism of Chromobacterium violaceum, inhibits autophagy in melanoma cells and consequently, stimulates death by apoptosis, in this project we will focus on 4 fronts: I) Assess whether the action of violacein is long lasting in 3D culture; II) Assess whether the presence of cells from the microenvironment affects the action of violacein in melanoma cells; III) Check if the Drug holiday therapeutic regimen, in which violacein in combination with Vemurafenib will be employed, is effective; IV) Examine whether violacein interferes with the level of Fatty Acid Synthase, a key enzyme in the synthesis of fatty acidsand considered as relevant in melanoma. Thus, it is expected that violacein will act as a sensitizing agent and, therefore, propiciates the use of lower vemurafenibe concentrations, and guarantees the response rate, which is relevant, regarding the patient's quality of life and the general cost of treatment. In addition, it is also expected that the study will alllow to identify markers (FASN and autophagic pathway proteins) for monitoring the effectiveness of melanoma treatment.

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