Mechanisms of Prolonged Initial Disease-Free Survival in Glioblastoma
Prolonged survival for patients diagnosed with glioblastoma multiforme (GBM) is exceedingly rare, with approximately 2 percent of patients surviving beyond five years.
Approximately one-third of patients with prolonged survival have a more indolent subtype of glioblastoma multiforme governed by mutation of isocitrate dehydrogenase (IDH). The remainder of long survivors have tumors that are typically associated with less than a six-month median initial progression-free survival (PFS) after aggressive surgery, radiation therapy (RT) and temozolomide (TMZ) therapy.
The focus of this application is to define the molecular mechanisms that result in extended initial progression-free survival in these rare patients with non-IDH mutant tumors.
To study the spectrum of treatment efficacy in glioblastoma multiforme, the Mayo Clinic Brain Cancer SPORE Grant has developed a panel of 43 primary tumor xenografts derived from patients with newly diagnosed primary glioblastoma multiforme. Three of these models (GBM 5, 75 and 84) were derived from patients with long initial progression-free survival, and each demonstrates unique hypersensitivity to cytotoxic therapy.
These results support the hypothesis that prolonged progression-free survival, in at least some patients, results from a unique sensitivity to initial therapy and not just from a generally indolent tumor biology.
In this application, patient tumors and xenograft models will be analyzed with next-generation sequencing (NGS) and functional proteomic tools, and then the xenograft models will be manipulated to robustly define mechanisms of hypersensitivity to radiation therapy and temozolomide therapy.
The planned aims are:
- Aim 1: A collection of 15 samples from long-surviving patients will be analyzed by whole-exome sequencing (WES) and mRNA-seq, and paired patient-xenograft samples will be subjected to a more detailed molecular landscape analysis with whole-genome sequencing and epigenomic profiling. Through an integrated analysis of these data and comparison to WES/mRNA-seq data from short survivors in TCGA, mechanistic hypotheses linked to prolonged disease control will be generated that will be tested in subsequent aims.
- Aim 2: Test mechanisms of extreme therapy sensitivity in the GBM 5, 75 and 84 xenograft models. Integrated next-generation sequencing and functional proteomic analyses will define putative mechanisms of hypersensitivity, and manipulation of gene expression then will be used to define the importance of specific pathways on therapy response. The ultimate goal of this application is to translate an understanding of molecular mechanisms associated with prolonged disease control into novel therapeutic strategies that could significantly enhance the efficacy of therapy for typical glioblastoma multiforme tumors.
- Aim 3: Use the insights gained from aims 1 and 2 to design a custom shRNA library, and then use an in vivo shRNA screen and subsequent validation studies to define pathway targets that can increase significantly the efficacy of radiation therapy, temozolomide therapy or both.