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Genetic mechanisms involved in chemotherapy resistance in metastatic osteosarcoma

Grant number: 16/01718-0
Support type:Scholarships in Brazil - Doctorate
Effective date (Start): May 01, 2017
Effective date (End): September 24, 2020
Field of knowledge:Health Sciences - Medicine - Medical Clinics
Cooperation agreement: Coordination of Improvement of Higher Education Personnel (CAPES)
Principal researcher:Silvia Regina Caminada de Toledo
Grantee:Alini Trujillo Paolillo
Home Institution: Escola Paulista de Medicina (EPM). Universidade Federal de São Paulo (UNIFESP). Campus São Paulo. São Paulo , SP, Brazil
Associated scholarship(s):19/18670-9 - Understanding the tumor microenvironment of osteosarcoma, BE.EP.DR

Abstract

Osteosarcoma (OS) is a malignant bone tumor derived from primitive mesenchymal cells and the most common in children and adolescents. Despite progress in OS treatment in recent decades, it has reached a plateau. The most recent clinical studies, which are focused on improved outcomes, through the intensification of therapy or incorporation of new therapeutic agents, have not been successful. Thus, the goal has been identifying biological changes that may serve as prognostic factors and therapeutic targets, allowing changes in therapy based on risks, thus improving the survival in high-risk patients. In general, patients nonmetastatic at diagnosis present 70% of overall survival in 5 years, while patients with pulmonary metastases at diagnosis present 31.6%, whereas the presence of metastases at diagnosis is an important prognostic factor. Therefore, our aim is to analyze the pharmacogenomics in OS metastasis, as well as establishing two cell lines from primary and metastatic tumor, both from the same patient, to enable future assays regarding response to chemotherapy and cell mechanisms, allowing the analysis of changes that may occur from the same cell of origin. The established OS cell lines (KHOS, Saos-2, U2-OS, MG-63 e M-OS) will be analyzed and separated by FACS (Fluorescence-Activated Cell Sorting) methodology according ALDH activity, a stem cell marker. The cell lines will be treated with cisplatin, doxorubicin and methotrexate, that are drugs used in OS treatment to analyze its efficacy in both groups, low and high activity of ALDH marker. In OS samples obtained from patients, 30 fragments of tumor resected in surgery and 30 fragments of metastatic tumor resected in thoracotomy, will be used to gene expression analysis by qRT-PCR, in genes that are important in pharmacokinetics and pharmacodynamics process to drugs used in OS treatment. The gene that will present the most significant result will submit to sequencing by Sanger Method, thus allowing analysis of possible genetic changes which is responsible for modification in the gene expression pattern. (AU)

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