A cell type-selective apoptosis-inducing small molecule for the treatment of brain cancer.

Glioblastoma multiforme (GBM; grade IV astrocytoma) is the most prevalent and aggressive form of primary brain cancer. A subpopulation of multipotent cells termed GBM cancer stem cells (CSCs) play a critical role in tumor initiation, tumor maintenance, metastasis, drug resistance, and recurrence following surgery. Here we report the identification of a small molecule, termed RIPGBM, from a cell-based chemical screen that selectively induces apoptosis in multiple primary patient-derived GBM CSC cultures. The cell type-dependent selectivity of this compound appears to arise at least in part from redox-dependent formation of a proapoptotic derivative, termed cRIPGBM, in GBM CSCs. cRIPGBM induces caspase 1-dependent apoptosis by binding to receptor-interacting protein kinase 2 (RIPK2) and acting as a molecular switch, which reduces the formation of a prosurvival RIPK2/TAK1 complex and increases the formation of a proapoptotic RIPK2/caspase 1 complex. In an orthotopic intracranial GBM CSC tumor xenograft mouse model, RIPGBM was found to significantly suppress tumor formation in vivo. Our chemical genetics-based approach has identified a drug candidate and a potential drug target that provide an approach to the development of treatments for this devastating disease.

Patterns of care and survival for glioblastoma patients in the Veterans population.

Survival outcomes and patterns of care for brain tumor patients in the USA Veterans population have not been previously published and the extent of variation in outcomes between Veterans and the rest of the USA is currently unknown. The Veterans healthcare administration (VA) provides comprehensive care to Veterans and their families and maintains the Veterans affairs central cancer registry (VACCR). This was a retrospective review of microscopically-confirmed, supratentorial glioblastoma multiforme in male Veterans actively followed by the VACCR; survival was analyzed and compared to a national cohort from the surveillance, epidemiology and end results program. We analyzed 1,219 Veterans with glioblastomas diagnosed between 1997 and 2006. Median survival was 6.5 months and 1, 2, and 5 years survival rates were 26.8, 5.4, and 0.5%, respectively. Patients receiving all three treatment modalities (surgical resection, radiotherapy, and chemotherapy) did best; these findings remained true among patients aged 70 and older such that these patients had an overall survival similar to those age <70. A comparable national cohort had longer median survival (9.0 months) and greater 1, 2, and 5 years survival rates (37.8, 12.8, and 4.1%) than the VA cohort. Survival and patterns of care are presented for the first time for Veterans with glioblastoma multiforme. In conclusion, we found that more aggressive therapy was associated with better survival, even among elderly Veterans and whether compared overall or by age group, VA patients showed decreased survival relative to a national cohort. We believe this potential disparity warrants further investigation.