Abstract Date: 5/2/2015
Wajd N. Al-Holou, MD
Tom Mikkelsen, MD
Roeland Verhaak, PhD
Brian Ross, PhD
Alnawaz Rehentulla, PhD (Ann Arbor, MI)
IntroductionDespite advancements in the treatment of glioblastoma multiforme(GBM), mean survival continues to be around 15 months with most patients developing recurrence. The goal of this study was to evaluate a clinically relevant mouse model and treatment scheme to recapitulate and analyze tumor recurrence in GBM.
Methods Cultured, patient-derived primary GBM-neurosphere cells were dissociated and implanted intracranially into athymic nude mice. Tumor volume was measured regularly with MRI(9.4T). Mice were randomized into treatment groups with combinations of radiation (IR) and temozolomide (TMZ) once their tumor volume reached 20-30mm3. Samples were collected pre-treatment and post-recurrence using a novel MRI-guided biopsy technique. The tumors were analyzed using whole genome RNA sequencing and validation using biochemical studies to delineate genomic basis for treatment resistance.To confirm the therapeutic resistant phenotype of recurrent tumors, pre-treatment and post-treatment tumors were implanted into immunodeficient mice.
ResultsDespite an initial response with TMZ/IR, all animals had recurrence towards the end of treatment. Pre-treatment and post-treatment(recurrence) samples were analyzed with RNAseq. Genes involved in cell adhesion, neuronal differentiation/development and cellular morphogenesis were dominant in the upregulated clusters. Transcriptome profiling revealed that TMZ/IR resistance might be related to an upregulation of a network of genes within the mesenchymal signature and downregulation of genes involved in cell death. It is conceivable that as tumors develop TMZ/IR resistance, tumor cells would acquire capability to avoid cell death.
We have developed a novel recurrence model of GBM and used an MRI-based stereotactic biopsy technique with RNAseq to genetically compare paired pre-treatment and recurrent GBMs.
Article ID: AA-31544