| Grant number: | 16/09077-4 |
| Support Opportunities: | Scholarships in Brazil - Doctorate (Direct) |
| Start date: | August 01, 2016 |
| End date: | July 31, 2021 |
| Field of knowledge: | Biological Sciences - Biochemistry - Chemistry of Macromolecules |
| Principal Investigator: | Sandra Martha Gomes Dias |
| Grantee: | Renna Karoline Eloi Costa |
| Host Institution: | Centro Nacional de Pesquisa em Energia e Materiais (CNPEM). Campinas , SP, Brazil |
Abstract Breast cancer is the most diagnosed type of cancer in women, with an estimated incidence of approximately 3.2 million cases a year by 2050. The triple-negative subtype (Triple Negative Breast Cancer, TNBC), characterized by low expression / no detection of hormone receptors estrogen (ER), progesterone (PR) and growth factors (Her2) is the most common among young women, whose characteristics are more aggressive, larger, greater chance of metastasis and a worse prognosis most likely to relapse. Reprogramming metabolism in tumor cells can provide targets for the treatment of cancer. Among them, we highlight the activation of glycolysis (even in the presence of oxygen), with increased lactate secretion and cataplerose of the tricarboxylic acid cycle (TCA) to provide intermediate important biosynthetic pathways. In the specific triple negative subtype, glutaminase, the first metabolization pathway of the amino acid glutamine, has emerged as a promising target. The amino acid glutamine is versatile in the cells and, in addition to acting as the main nitrogen donor for the synthesis of nucleotides, amino acids and glutathione, is also an important carbon source for anaplerosis (and reestablishment) of the TCA. Two genes (and four isoforms) codes to glutaminase, being glutaminase C (GAC) the primary target, as has important pro-tumor functions. In fact, the compound CB-839 (GAC inhibitor) is already undergoing phase I clinical testing in solid tumors (such as triple-negative breast) and haematological tess. After a campaign of High Throughput Screening (HTS) performed in the laboratory of the advisor of this proposal with a library of 30 thousand compounds having isoform GAC as target, several hits were identified by inhibition above 50% of the enzyme. Eleven compounds were previously acquired and evaluated for IC50 for the enzyme and on cell proliferation of tumor models TN, not-TN and non-tumor models (breast epithelium). In this project, we propose to evaluate analogues of the most promising compounds for cellular assays to assess tumor-selective cytotoxicity and action on the target. With the results, which will be combined with complementary biochemical studies that will be conducted in the laboratory, we aim to advance the development of potent inhibitory molecules acting on the glutaminase. (AU) | |
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