Identification and therapeutic targeting of novel transforming pathways in human glioblastoma multiforme

Glioblastoma multiforme (GBM) is the most common primary brain malignancy with approximately 9,000 cases diagnosed per year in the U.S. This devastating cancer is virtually uniformly lethal with an average survival of less than one year after diagnosis. The current standard of care for newly diagnosed GBM is surgical resection, followed by adjuvant radiotherapy plus chemotherapy with temozolomide. This treatment is only marginally successful, rarely extending lifespan after diagnosis past eighteen months. While several oncogenes (e.g. EGFR, PDGFRA) and tumor suppressor genes (e.g. TP53, CDKN2A, PTEN) that contribute to gliomagenesis have been identified, no therapeutics that specifically target these known lesions have yet proved beneficial. As such, a better understanding of the molecular pathogenesis of GBM is required to identify new molecular targets and develop new effective treatments.;To discover novel genes whose alterations drive gliomagenesis, we used Affymetrix SNP microarrays to identify copy number alterations present in a panel of GBM primary tumors, primary xenografts, primary cultures, and cell lines. This analysis demonstrated a significant sample type bias in the frequency of common copy number alterations in GBM and suggested that primary tumors and xenografts are best for the identification of amplifications, whereas xenografts and cell lines are superior for the identification of homozygous deletions.;This analysis also led to identification of homozygous deletions of two genes (PTPRD and CDKN2C).not previously known to be altered in GBM. Using directed sequencing, we subsequently identified frequent somatic mutations of PTPRD, encoding a receptor-type protein tyrosine phosphatase, in both GBM and melanoma tumor samples, demonstrating that phosphatase inactivation (and not just kinase activation) is a major contributor to tumorigenesis. The discovery of frequent deletions of the CDKN2C gene encoding p18INK4c, a homolog of the well characterized CDKN2A/p16INK4a tumor suppressor, identified an additional mechanism leading to aberrant activation of cdk4/6 in GBM and provided further impetus for the testing of cyclin-dependent kinase (cdk)-specific inhibitors against GBM. We found that the cdk4/6-specific inhibitor PD-0332991 potently arrested the growth of all Rb-proficient GBM cells in vitro and intracranial xenografts in vivo . These findings prompted a clinical trial testing the effectiveness of PD-0332991 in GBM patients.