Dados do Resumo

Título

Identification of molecular targets in soft tissue sarcomas: evaluation of mutations with therapeutic potential in patient-derived experimental models.

Introdução

Soft tissue sarcomas (STS) are rare neoplasms with different morphological patterns of mesenchymal cells and can evolve with high rates of morbidity and mortality. High-grade tumors have a worse prognosis due to their high metastatic capacity (mainly to the lungs), with a median survival not exceeding 15% in five years. The limited effectiveness of current treatments is partly due to a lack of comprehensive understanding of the biological mechanisms driving these tumors. Therefore, identifying targets that can modulate the biology of STS holds promise for significant advancements in treatment. Our group has generated over 30 patient-derived xenograft (PDX) models representing various STS subtypes. Additionally, we have established 3D primary cultures, also known as patient-derived organoids (PDOs), which complement the PDX models by replicating the tumor heterogeneity observed in patient tumors.

Objetivo

The objective of this project is to use data generated from exome sequencing of undifferentiated spindle sarcomas to identify potential vulnerabilities associated with mutations in specific target genes or signaling pathways. The goal is to uncover pharmacologically actionable targets that could be addressed through therapeutic interventions.

Métodos

Tumor samples from patients, as well as patient-derived xenografts (PDX) and primary cultures, were subjected to whole exome sequencing using the Agilent SureSelect XT library on an Illumina platform. Data processing was performed excluding murine reads, with variant identification and analysis conducted using VarSeq software. For cell culture, both fresh and cryopreserved tissues were utilized to establish monolayer and 3D cultures. Cell viability assays will be performed on these cultures using various drug combinations. Promising targets identified through these assays will be further validated through in vivo tumor growth assays in PDX models.

Resultados

Exome sequencing data was generated from four sets of samples: patient tumors, patient-derived xenografts (PDX), and primary cultures of undifferentiated spindle sarcomas. Several common variants were identified and will be analyzed to pinpoint potential drug targets that could sensitize tumor cells. We have also established initial conditions for cell viability assays using doxorubicin, the first-line therapy for metastatic sarcoma.

Conclusões

We expect to uncover novel targets with significant clinical potential for the treatment of soft tissue sarcoma. By identifying targets with high prognostic value and predictive power, we aim to enhance our understanding of STS and improve therapeutic strategies. Our efforts will pave the way for more effective and personalized treatment approaches, ultimately benefiting patient outcomes in this challenging area of oncology.

Palavras Chave

PDX soft tissue sarcoma therapeutic strategies genes doxorubicin