Scholarlink

Background <p>Gliomas are the most common primary brain tumors in adults and encompass a spectrum from IDH-mutant gliomas to highly aggressive IDH-wild type glioblastomas (GBM). Despite advances in our understanding of glioma biology, GBM remains largely incurable, with a median overall survival (mOS) of approximately 15 months and minimal improvements over recent decades. The current standard of care, maximal surgical resection followed by radiotherapy and temozolomide (TMZ) chemotherapy, has proven insufficient, and experimental approaches such as immune checkpoint inhibitors and CAR-T cell therapies have also failed to provide meaningful survival benefits. These limitations highlight the urgent need for innovative, patient-specific platforms to evaluate novel therapeutic strategies.</p> Methods <p>In this study, we established patient-derived glioma organoids (GOs) from 61 patients, including both IDH-mutant gliomas (GOmut) and IDH-wild type glioblastoma (GOwt). These organoids were characterized by a variety of techniques against their parental tumors. Afterwards, we performed <i>in silico</i> drug discovery with paired RNA-seq data and validated the results with diverse glioma models.</p> Results <p>GOs recapitulated the cellular heterogeneity, histological architecture, and molecular signatures of their parental tumors, including the preservation of clinically relevant features such as immune profiles, vascular structures, and tumor subtype. Notably, GOmuts retained the IDH mutation over extended culture periods. Importantly, GOs maintained resistance to standard chemotherapeutic agents, mirroring the limited response of gliomas to conventional chemotherapy. Our unbiased <i>in silico</i> screening via the DiSCoVER platform applied to RNA-seq data from paired tumors and GOs identified alectinib, dabrafenib, and ruxolitinib as promising candidates. All three compounds proved effective in in vitro cytotoxicity assays, with alectinib and ruxolitinib displaying significant antitumoral effects in vitro.</p> Conclusions <p>Our findings establish GOs as a clinically relevant and biologically faithful platform for therapeutic screening in glioma. By integrating transcriptomics-based drug discovery with a patient-specific organoid model, we present an easy to implement platform for more effective and personalized treatments for glioma patients. Our findings also support the inclusion of two compounds, alectinib and ruxolitinib, in future clinical investigations.</p>

错误：搜索内容不能为空，请输入英文关键词
错误：关键词超出字数限制，请精简
高级检索

Precision oncology in a dish: patient-derived glioma organoids to guide novel therapeutic strategies

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年2月6日

查看全文
  • Alvaro Monago-Sánchez,
  • Laura Mateos-Madrigal,
  • Josefa Carrión-Navarro,
  • Ana Hernández-Martínez,
  • Carlos Martínez-Riveiro,
  • María Castelló-Pons,
  • María Victoria Pacheco-Fuenmayor,
  • Raquel Gutiérrez-González,
  • Noemí Lomillos-Prieto,
  • Ricardo Prat-Acín,
  • Santiago Gil-Robles Mathieu,
  • Cristina Aracil-González,
  • Angel Pérez-Núñez,
  • Francisco Pérez-Rodríguez,
  • Pilar Sánchez-Gómez,
  • Beatriz Martín-Jouve,
  • Antonio J. Sánchez-López,
  • Noemi García-Romero,
  • Ángel Ayuso-Sacido

摘要

Background

Gliomas are the most common primary brain tumors in adults and encompass a spectrum from IDH-mutant gliomas to highly aggressive IDH-wild type glioblastomas (GBM). Despite advances in our understanding of glioma biology, GBM remains largely incurable, with a median overall survival (mOS) of approximately 15 months and minimal improvements over recent decades. The current standard of care, maximal surgical resection followed by radiotherapy and temozolomide (TMZ) chemotherapy, has proven insufficient, and experimental approaches such as immune checkpoint inhibitors and CAR-T cell therapies have also failed to provide meaningful survival benefits. These limitations highlight the urgent need for innovative, patient-specific platforms to evaluate novel therapeutic strategies.

Methods

In this study, we established patient-derived glioma organoids (GOs) from 61 patients, including both IDH-mutant gliomas (GOmut) and IDH-wild type glioblastoma (GOwt). These organoids were characterized by a variety of techniques against their parental tumors. Afterwards, we performed in silico drug discovery with paired RNA-seq data and validated the results with diverse glioma models.

Results

GOs recapitulated the cellular heterogeneity, histological architecture, and molecular signatures of their parental tumors, including the preservation of clinically relevant features such as immune profiles, vascular structures, and tumor subtype. Notably, GOmuts retained the IDH mutation over extended culture periods. Importantly, GOs maintained resistance to standard chemotherapeutic agents, mirroring the limited response of gliomas to conventional chemotherapy. Our unbiased in silico screening via the DiSCoVER platform applied to RNA-seq data from paired tumors and GOs identified alectinib, dabrafenib, and ruxolitinib as promising candidates. All three compounds proved effective in in vitro cytotoxicity assays, with alectinib and ruxolitinib displaying significant antitumoral effects in vitro.

Conclusions

Our findings establish GOs as a clinically relevant and biologically faithful platform for therapeutic screening in glioma. By integrating transcriptomics-based drug discovery with a patient-specific organoid model, we present an easy to implement platform for more effective and personalized treatments for glioma patients. Our findings also support the inclusion of two compounds, alectinib and ruxolitinib, in future clinical investigations.