Dados do Trabalho

Título

Patient-derived renal cell carcinoma xenograft organoids (PDXO) as a possible tool to predict drug sensitivity in personalized medicine.

Introdução

Renal cell carcinoma (RCC) comprises up to 3% of human adult malignancies. Nephrectomy is a curative option for patients with localized tumors. However, metastatic disease reduces the overall survival to 20% in five years. In the clinic, few approved targeted therapeutic drugs and immunotherapy benefits only a small percentage of patients. Among individuals, targeted therapy outcomes vary consistently due to intertumoral heterogeneity

Objetivo

The AC Camargo Biobank of Patient-derived xenograft (PDX) encompasses several RCC cases allowing us to develop a model of 3D patient-derived xenograft organoid (PDXO) established directly through in vitro culture of PDX tumors. These tumor organoids are self-renewal 3D structures that prompted us to examine the feasibility of PDXO to evaluate drug sensitivities as a powerful tool to test personalized treatment strategies for RCC.

Métodos

Tumors were obtained from the PDX biobank (fresh and snap-frozen tissue) and the PDXO were established after enzymatic digestion of the corresponding tumor. The obtained cell pellet was seeded in growth factor-reduced Geltrex ® and cultured in kidney organoid medium. After expansion, organoids morphology and immunohistochemical features were evaluated to confirm similarity with the parental PDX tumor. We also performed drug sensitivity assays in PDXO with stand-of-care drugs.

Resultados

The preliminary results from 8 clear cell RCC PDX tumors showed that PDXO were generated at an efficiency of 50% (growth + expansion). The morphology and immunostaining of PDXOs matched with the original PDX tumor, confirming a high similarity of both models. Dose-response curves were obtained by treating the four generated PDXO lines with sunitinib (multiple tyrosine kinase inhibitor) and everolimus (mTOR inhibitor). The PDXO lines showed different drug sensitivity for each drug. We are now collecting the clinical outcomes of patients to establish translational correlations between PDXO drug sensitivity and individual clinical responses to treatment.

Conclusões

Predictive drug testing with PDXO is feasible. Positive results will allow us to try to generate patient-derived organoids (PDO) directly from tumor patient biopsies to obtain a proof-of-concept of their possible application as a predictive tool of personalized medicine in RCC. To our understanding, this is the first Brazilian study to validate the use of PDXO to predict therapeutic response.

Palavras-chave

renal cell carcinoma; patient-derived xenograft organoid; personalized medicine

Financiador do resumo

Instituto Nacional para Ciência e Tecnologia em Oncogenômica e Inovação Terapêutica (FAPESP - 2014/50943-1, CNPq - 465682/2014-6); FAPESP (grant: 2021/05037-6).