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Characterization of the role of tumor metabolism in the resistance of human melanoma to Vemurafenib

Grant number: 17/12620-4
Support Opportunities:Scholarships in Brazil - Doctorate
Effective date (Start): September 01, 2017
Effective date (End): June 30, 2019
Field of knowledge:Biological Sciences - Biochemistry - Metabolism and Bioenergetics
Principal Investigator:Céline Marques Pinheiro
Grantee:Marina Pereira Dias
Host Institution: Hospital do Câncer de Barretos. Fundação Pio XII (FP). Barretos , SP, Brazil

Abstract

The incidence of skin cancer is increasing worldwide, with melanoma being the most lethal type due to its great metastatic potential. B-RAF is one of the major oncogenes involved in the tumorigenesis of this type of tumor, stimulating highly proliferative phenotypes. This phenotype is supported in great part by aerobic glycolysis, also known as Warburg effect, besides being also described an important role of glutamine metabolism. The development of B-RAF inhibitors, such as vemurafenib, has brought a breakthrough in the treatment of these tumors. Despite a high response rate, the vast majority of tumors have been described to develop resistance to this drug. Thus, the therapeutic efficiency would greatly benefit from the understanding of the molecular mechanisms involved in the aggressiveness and resistance to the existing treatments. In this context, this project aims to evaluate the role of tumor metabolism in the resistance of melanoma cells to vemurafenib. For this, we will evaluate a) the expression of proteins related to the glycolytic and glutamine metabolism in human samples of melanoma, before and after treatment with vemurafenib, using immunohistochemistry; b) the metabolic profile of vemurafenib resistant parent lines by means of Western blotting, immunocytochemistry, and quantification of glucose and glutamine consumption, as well as lactate production; c) the effect of the combined treatment of vemurafenib with inhibitors of metabolism on viability, proliferation, migration and cell invasion, and colony formation capacity; d) the effect of combined treatment on tumor formation and growth and induction of angiogenesis using an in vivo model (chorioallantoic membrane). With this data, we hope to contribute to elucidate the mechanisms involved in melanoma cells' resistance to current treatment protocols, focusing on metabolic alterations, and propose alternatives that aim to overcome such mechanisms. (AU)

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Scientific publications
(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)
VITAL, PATRIK DA SILVA; BONATELLI, MURILO; DIAS, MARINA PEREIRA; DE SALIS, LARISSA VEDOVATO VILELA; PINTO, MARIANA TOMAZINI; BALTAZAR, FATIMA; MARIA-ENGLER, SILVYA STUCHI; PINHEIRO, CELINE. 3-Bromopyruvate Suppresses the Malignant Phenotype of Vemurafenib-Resistant Melanoma Cells. INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES, v. 23, n. 24, p. 17-pg., . (15/25351-6, 19/07502-8, 19/14189-4, 16/13021-4, 16/10821-0, 17/12620-4)

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