{"database":"biostudies-literature","file_versions":[],"scores":null,"additional":{"submitter":["McCord M"],"funding":["National Institute of Neurological Disorders and Stroke","National Cancer Institute","NINDS NIH HHS","NCI NIH HHS"],"pagination":["5494"],"full_dataset_link":["https://www.ebi.ac.uk/biostudies/studies/S-EPMC9688760"],"repository":["biostudies-literature"],"omics_type":["Unknown"],"volume":["14(22)"],"pubmed_abstract":["Adult-type diffusely infiltrating gliomas, of which glioblastoma is the most common and aggressive, almost always recur after treatment and are fatal. Improved understanding of therapy-driven tumor evolution and acquired therapy resistance in gliomas is essential for improving patient outcomes, yet the majority of the models currently used in preclinical research are of therapy-naïve tumors. Here, we describe the development of therapy-resistant IDH-wildtype glioblastoma patient-derived xenografts (PDX) through orthotopic engraftment of therapy naïve PDX in athymic nude mice, and repeated in vivo exposure to the therapeutic modalities most often used in treating glioblastoma patients: radiotherapy and temozolomide chemotherapy. Post-temozolomide PDX became enriched for C>T transition mutations, acquired inactivating mutations in DNA mismatch repair genes (especially MSH6), and developed hypermutation. Such post-temozolomide PDX were resistant to additional temozolomide (median survival decrease from 80 days in parental PDX to 42 days in a temozolomide-resistant derivative). However, temozolomide-resistant PDX were sensitive to lomustine (also known as CCNU), a nitrosourea which induces tumor cell apoptosis by a different mechanism than temozolomide. These PDX models mimic changes observed in recurrent GBM in patients, including critical features of therapy-driven tumor evolution. These models can therefore serve as valuable tools for improving our understanding and treatment of recurrent glioma."],"journal":["Cancers"],"pubmed_title":["Modeling Therapy-Driven Evolution of Glioblastoma with Patient-Derived Xenografts."],"pmcid":["PMC9688760"],"funding_grant_id":["R01NS122395","R01NS115403","R01NS102669","R01NS095642","F32 CA264883","R01NS118039","P50CA221747","R01NS117104","R01NS122375","R50CA221848"],"pubmed_authors":["Eckerdt FD","Cheng SY","Heimberger AB","McCord M","James CD","Bartom E","Sears T","Baran A","Balyasnikova IV","Burdett K","Horbinski C","Stupp R","Ahmed A","McCortney K","Sarkaria JN"],"additional_accession":[]},"is_claimable":false,"name":"Modeling Therapy-Driven Evolution of Glioblastoma with Patient-Derived Xenografts.","description":"Adult-type diffusely infiltrating gliomas, of which glioblastoma is the most common and aggressive, almost always recur after treatment and are fatal. Improved understanding of therapy-driven tumor evolution and acquired therapy resistance in gliomas is essential for improving patient outcomes, yet the majority of the models currently used in preclinical research are of therapy-naïve tumors. Here, we describe the development of therapy-resistant IDH-wildtype glioblastoma patient-derived xenografts (PDX) through orthotopic engraftment of therapy naïve PDX in athymic nude mice, and repeated in vivo exposure to the therapeutic modalities most often used in treating glioblastoma patients: radiotherapy and temozolomide chemotherapy. Post-temozolomide PDX became enriched for C>T transition mutations, acquired inactivating mutations in DNA mismatch repair genes (especially MSH6), and developed hypermutation. Such post-temozolomide PDX were resistant to additional temozolomide (median survival decrease from 80 days in parental PDX to 42 days in a temozolomide-resistant derivative). However, temozolomide-resistant PDX were sensitive to lomustine (also known as CCNU), a nitrosourea which induces tumor cell apoptosis by a different mechanism than temozolomide. These PDX models mimic changes observed in recurrent GBM in patients, including critical features of therapy-driven tumor evolution. These models can therefore serve as valuable tools for improving our understanding and treatment of recurrent glioma.","dates":{"release":"2022-01-01T00:00:00Z","publication":"2022 Nov","modification":"2025-04-19T22:59:40.399Z","creation":"2025-04-19T22:59:40.399Z"},"accession":"S-EPMC9688760","cross_references":{"pubmed":["36428586"],"doi":["10.3390/cancers14225494"]}}