Dados do Resumo

Título

Application of patient-derived xenograft organoids (PDXO) as a preclinical model for drug screening and identification of treatment-induced vulnerabilities

Introdução

Patient-derived organoids (PDO) and patient-derived xenografts (PDX) are widely recognized for their ability to recapitulate morphology, genetic heterogeneity, and patient's tumor response to treatment. These models provide complementary features, with PDOs closely mirroring tumor architecture and cellular behavior, while PDXs effectively capture tumor evolution and metastasis dynamics. The AC Camargo Cancer Center PDX Biobank included several cases of clear cell Renal Cell Carcinoma (ccRCC) with the patient's complete clinical allowing the generation of PDX organoids (PDXOs), and high-throughput drug screening.

Objetivo

The present work aims to a) establish and validate ccRCC PDXO to predict tumor response to standard-of-care treatments and b) explore drug vulnerabilities and synthetic lethality approaches in BAP1-mutated tumors.

Métodos

Twelve PDX samples (fresh or cryopreserved) were enzymatically digested, resuspended, seeded in growth factor-reduced Geltrex®, and cultured in a kidney organoid medium. The generated PDXOs were characterized using histology and immunohistochemistry approaches. Cell viability assays were conducted on three PDXOs to assess therapeutic potential, evaluate their sensitivity to stand-of-care Tyrosine Kinase Inhibitor (Sunitinib), and associate with patients' clinical responses. In addition, BAP1 T517A and BAP1 WT PDXO were treated with Olaparib (PARP inhibitor) and Vorinostat (HDAC inhibitor).

Resultados

The success of PDXOs' growth and expansion reached 60%, demonstrating the reliability of our methodology. We characterized five PDXO lines, highlighting the robustness of our approach. Histologic and immunohistochemistry analysis confirmed that both PDX and PDXOs preserved the morphological characteristics of the matched patient tumors. When treated with Sunitinib according to the patient's therapy regimens, the PDXOs exhibited sensitivities that closely mirrored the patients' clinical patients. The preliminary results also show that BAP1 T517A PDXO were more sensitive to PARPi (Olaparib) and HDACi (Vorinostat) treatments than wild-type BAP1 PDXO.

Conclusões

These results indicate that PDXOs' response to Sunitinib treatment correlates with patients' clinical response. We suggest that BAP1 mutation in PDXOs confers drug vulnerability to Olarapib and Vorinostat treatments. Together, these data suggest that PDXOs are import tools to predict patient response to therapies.

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).

Palavras Chave

Renal cell carcinoma; patient-derived xenograft organoid; precision medicine