The vast majority of newly diagnosed glioblastoma (GBM) patients receive treatment with the DNA alkylator temozolomide (TMZ), subsequent to surgical debulking of primary tumor. The favorable drug profile for TMZ, which includes oral administration, excellent CNS distribution, and minor side effects, combined with the modest survival benefit it provides to a substantial fraction of GBM patients, is likely to ensure it’s routine use in clinical neuro-oncology for many years to come. However, it is well established that TMZ is a mutagen, and the published results of others suggest that TMZ therapy may ultimately produce a more aggressive and therapy-resistant derivative of the initial tumor. Though an intriguing possibility, understanding of the consequences of TMZ treatment of GBM is modest at best. That is to say we know very little regarding what TMZ therapy does to a GBM. The research associated with this project will address this knowledge deficiency by generating and validating recurrent TMZ-resistant GBM tumor models that can be propagated for extended study, both by the PI of this proposal as well as by other investigators interested in improved understanding of and treatment outcomes for recurrent GBM. A central hypothesis associated with the studies proposed here is that some of TMZ-associated mutations will create points of tumor susceptibility to therapeutic intervention, and our research plan will determine whether this is the case. If successful, not only will our research generate new models for recurrent, TMZ-resistant GBM, but it will as well provide information important to extending the length and quality of life for this patient population.
|Effective start/end date||3/1/16 → 2/28/22|
- National Institute of Neurological Disorders and Stroke (5R01NS095642-05)