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 language | English (US) |
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Article number | 5494 |
Journal | Cancers |
Volume | 14 |
Issue number | 22 |
DOIs | |
State | Published - Nov 2022 |
Funding
This work was supported by NIH grants R01NS095642 (C.D.J.); U01CA227954, R24NS092940 (J.N.S.); R01NS115403, R01NS125318, R21NS126810, R21NS122375 (S.-Y.C.); R01NS102669, R01NS117104, R01NS118039 (C.H.); R50CA221848 (E.B.); R01NS122395, R01NS106379 (I.V.B.); and the Northwestern University SPORE in Brain Cancer P50CA221747.
Keywords
- CNS cancers
- DNA damage and repair
- chemotherapy
- drug resistance
- glioblastomas
- gliomas
- preclinical models
- tumor evolution
- xenograft models
ASJC Scopus subject areas
- Oncology
- Cancer Research