Modeling Therapy-Driven Evolution of Glioblastoma with Patient-Derived Xenografts

Matthew McCord, Elizabeth Bartom, Kirsten Burdett, Aneta Baran, Frank D. Eckerdt, Irina V. Balyasnikova, Kathleen McCortney, Thomas Sears, Shi Yuan Cheng, Jann N. Sarkaria, Roger Stupp, Amy B. Heimberger, Atique Ahmed, Charles David James, Craig Horbinski

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Article number5494
JournalCancers
Volume14
Issue number22
DOIs
StatePublished - Nov 2022

Keywords

  • chemotherapy
  • CNS cancers
  • DNA damage and repair
  • drug resistance
  • glioblastomas
  • gliomas
  • preclinical models
  • tumor evolution
  • xenograft models

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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