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

Grant number: 14/03684-0
Support Opportunities:Scholarships in Brazil - Master
Effective date (Start): November 01, 2014
Effective date (End): March 31, 2016
Field of knowledge:Biological Sciences - Biochemistry - Molecular Biology
Acordo de Cooperação: Coordination of Improvement of Higher Education Personnel (CAPES)
Principal Investigator:Olga Catarina Lopes Martinho
Grantee:Fernanda de Paula Cury
Host Institution: Hospital do Câncer de Barretos. Fundação Pio XII (FP). Barretos , SP, Brazil
Associated scholarship(s):15/02691-6 - Functional role of kit GNNK+ and GNNK- isoforms in glioblastoma, BE.EP.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 sohwed that GNNK isoform are frequently co-expressed in both glioblastoma cell lines and normal tissues, with GNNK- being the prevalent form in glioblastoma cell lines, whereas in normal brain tissues there is predominance of GNNK+ isoform, suggesting that GNNK- isoform could play a role in glioblastoma tumorigenesis. Hitherto, there are no reports assessing KIT GNNK isoforms functional role in both normal and tumor brain tissues.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 in glioblatoma. We believe that the outcomes of this project will be of the upmost relevance to clarify the role of KIT oncogene in glioblastoma biology and treatment and, importantly, they could lead to the identification of predictive biomarkers of 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)
MARTINHO, OLGA; SILVA-OLIVEIRA, RENATO; CURY, FERNANDA P.; BARBOSA, ANA MARTINS; GRANJA, SARA; EVANGELISTA, ADRIANE FEIJO; MARQUES, FABIO; MIRANDA-GONCALVES, VERA; CARDOSO-CARNEIRO, DIANA; DE PAULA, FLAVIA E.; et al. HER Family Receptors are Important Theranostic Biomarkers for Cervical Cancer: Blocking Glucose Metabolism Enhances the Therapeutic Effect of HER Inhibitors. THERANOSTICS, v. 7, n. 3, p. 717-732, . (14/03684-0)
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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