| Grant number: | 16/03634-9 |
| Support Opportunities: | Scholarships in Brazil - Post-Doctoral |
| Start date: | June 01, 2016 |
| End date: | May 31, 2019 |
| Field of knowledge: | Biological Sciences - Genetics - Human and Medical Genetics |
| Principal Investigator: | Rui Manuel Vieira Reis |
| Grantee: | Nathália Cristina Campanella |
| Host Institution: | Hospital do Câncer de Barretos. Fundação Pio XII (FP). Barretos , SP, Brazil |
Abstract The GIST are the most common mesenchymal tumors of the gastrointestinal tract. They are characterized by the presence of activating mutations of oncogenes KIT/ PDGFRA that induce constitutive activation of cell proliferation and survival pathways, and because of this are target by the molecular treatment imatinib, sunitibe and regorafenib. Our group previously identified an important prognostic factor in GIST, the raf kinase inhibitor protein (RKIP), whose loss of expression occurs in about 17% of GIST. Preliminary results from our group showed that the RKIP silencing in GIST cell line not promotes change in ERK protein expression and in this sense, other signaling pathways can be activated in a compensatory manner. In addition, studies have been showing that the imatinib and sunitibe therapy can modulate the tumor microenvironment that also is influenced by RKIP. In this context, the aim of this work is elucidate the biological and therapeutic impact of RKIP silencing in GIST. In addition, the interaction of tumor microenvironment and the therapy target, as the importance of RKIP silencing in this process, also will be evaluated. The evaluation of the differential expression of a gene panel involved in cancer will be done by the Nanostring platform. Proteomic analysis will be done to identify the differentially expressed proteins in tumor cell lines. Validation of the main proteins differentially cxpressed will be done in a series of patients with GIST by immunohistochemical analysis. In the next step, the biological and therapeutic impact of the RKIP silencing will be evaluate in vitro and in vivo. In addition, the co-culture with macrophages and the GIST cell lines will be established to evaluate the biological and therapeutic impact of RKIP silencing associated with tumor microenvironment tumoral in vitro and in vivo. Finally, the GIST cell lines will be treated with the IC50 dose to imatinib, sunitinib, and regorafenib to further evaluation of the therapeutic impact in vitro and in vivo. | |
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