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Functional role of kit GNNK+ and GNNK- isoforms in glioblastoma

Grant number: 15/02691-6
Support Opportunities:Scholarships abroad - Research Internship - Master's degree
Effective date (Start): May 16, 2015
Effective date (End): August 15, 2015
Field of knowledge:Biological Sciences - Biochemistry - Molecular Biology
Principal Investigator:Olga Catarina Lopes Martinho
Grantee:Fernanda de Paula Cury
Supervisor: Maria de Fátima Monginho Baltazar
Host Institution: Hospital do Câncer de Barretos. Fundação Pio XII (FP). Barretos , SP, Brazil
Research place: Universidade do Minho (UMinho), Portugal  
Associated to the scholarship:14/03684-0 - Functional role of kit GNNK+ and GNNK- isoforms in glioblastoma, BP.MS


Glioblastoma is the most common adult brain tumor and one of the deadliest human malignancies. The reason for this dark scenario, which has not changed significantly in the last 3 decades, is inherent to the biological properties of glioblastoma. Therefore, it is urgent to understand its molecular players in order to develop novel and targeted therapeutic strategies. KIT, a member of the receptor tyrosine kinase (RTK) family III, is involved with the tumorigenesis of some tumors and the existence of specific small molecule inhibitors for KIT made this protein a key molecular therapeutic target in cancer. In fact, unprecedented clinical efficacy has been attained in some tumors like gastrointestinal stromal tumor (GIST) patients, particular the ones harboring KIT activating mutations. However, we and others have performed an extensive analysis of KIT alterations in malignant gliomas, and showed the absence of KIT activating mutations and instead the presence of KIT gene amplification. Importantly, due to mRNA alternative splicing, KIT is expressed by two different functional isoforms, which are characterized by the presence (+) or absence (-) of a tetrapeptide sequence (GNNK) in the extracellular juxtamembrane region. They were shown to display distinct intracellular signaling features and also different tumorigenic transforming activities in mouse fibroblasts. Our preliminary results have showed difference in expression between glioblastoma cell lines and normal tissues, suggesting that GNNK- isoform could play a role in glioblastoma tumorigenesis. Thus, in the present project we aim to shed light on the functional and biological roles of KIT GNNK isoforms in glioblastomas. Specifically, we pretend to assess the tumorigenic role of each KIT isoform and to address whether the distinct KIT isoforms have different sensitivities to clinically available KIT inhibitors and evaluate the role in vivo of KIT isoforms through the CAM model and could lead to the identification of predictive biomarkers and anti-KIT therapy response. (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)
MIRANDA-GONCALVES, VERA; CARDOSO-CARNEIRO, DIANA; VALBOM, INES; CURY, FERNANDA PAULA; SILVA, VIVIANE ALINE; GRANJA, SARA; REIS, RUI M.; BALTAZAR, FATIMA; MARTINHO, OLGA. Metabolic alterations underlying Bevacizumab therapy in glioblastoma cells. ONCOTARGET, v. 8, n. 61, p. 103657-103670, . (14/03684-0, 15/02691-6)

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