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Molecular characterization of soft-tissue sarcomas: integration of translational preclinical models and functional study of genetic alterations with clinical relevance

Grant number: 18/25541-8
Support type:Regular Research Grants
Duration: June 01, 2019 - May 31, 2021
Field of knowledge:Health Sciences - Medicine
Principal Investigator:Tiago Góss dos Santos
Grantee:Tiago Góss dos Santos
Home Institution: A C Camargo Cancer Center. Fundação Antonio Prudente (FAP). São Paulo , SP, Brazil
Assoc. researchers: Andrea Bertotti ; Celso Abdon Lopes de Mello ; Giovana Tardin Torrezan ; Glaucia Noeli Maroso Hajj ; Israel Tojal da Silva ; Vilma Regina Martins

Abstract

Soft tissue sarcomas (STS) are rare neoplasms with different morphological patterns of mesenchymal cells that can evolve with high rates of morbidity and mortality. High-grade tumors larger than 10 cm and deep have a worse prognosis due their high metastatic capacity (mainly to the lungs), with median survival not exceeding 15%. The low efficacy in the treatment of these tumors is in part related to the little existing knowledge about the biological characteristics that govern these tumors. Therefore, the search for molecules capable of modulating the biology of these tumor types can bring substantial improvements to the treatment of the disease. For the development of new therapies, it is necessary to study the function of the molecular alterations peculiar to this group of tumors. In this sense, consortia such as The Cancer Genome Atlas (TCGA) make an immense contribution to providing the scientific community with the complete landscape of molecular alterations in thousands of patients with tumors, including sarcomas. However, for such initiatives to make sense, these studies need to be complemented with research into the role of specific tumor changes in order to identify potential therapeutic targets that could benefit patients. Therefore, the objective of this project is to establish an integrated, convergent and translational platform for STS. The structuring will be based on the exploration of TCGA data, preclinical experimental models (PDX, patient-derived xenografts e PDO, patient-derived organoids) and samples from A.C. Camargo Cancer Center patients. The identification of clinically relevant molecular alterations will be explored in cell lines, PDX and PDO. The identified targets that present potential for clinical application will be evaluated for their prognostic, predictive and therapeutic power. Therefore, the Lgr5 receptor (stem cells marker in intestinal crypts) has become a target because its increased expression in 15% of TCGA cases, highlighting its application as a potencial targeted therapy in STS. (AU)