Glioblastoma is both the most common and lethal primary malignant brain tumor. Extensive multiplatform genomic characterization has provided a higher-resolution picture of the molecular alterations underlying this disease. These studies provide the emerging view that “glioblastoma” represents several histologically similar yet molecularly heterogeneous diseases, which influences taxonomic classification systems, prognosis, and therapeutic decisions.

SUMMARY A hallmark feature of glioblastoma (GBM) is its strong self-renewal potential and immature differentiation state which contributes to its plasticity and therapeutic resistance. Here, integrated genomic and biological analyses identified PLAGL2 as a potent proto-oncogene targeted for amplification/gain in malignant gliomas. Enhanced PLAGL2 expression strongly suppresses neural stem cell (NSC) and glioma initiating cell (GIC) differentiation while promoting their self-renewal capacity upon differentiation induction. Transcriptome analysis revealed that these differentiation suppressive activities are attributable in part to PLAGL2 modulation of Wnt/β-catenin signaling. Inhibition of Wnt signaling partially restores PLAGL2-expressing NSC’s differentiation capacity. The identification of PLAGL2 as a glioma oncogene highlights the importance of a growing class of cancer genes functioning to impart stem cell-like characteristics in malignant cells.

Glioblastoma multiforme (GBM) is a fatal primary brain tumor harboring myriad genetic and epigenetic alterations. The recent multidimensional analysis of the GBM genome has provided a more complete view of the landscape of such alterations and their linked pathways. This effort has demonstrated that certain pathways are universally altered, but that the specific genetic events altered within each pathway can vary for each particular patient's tumor. With this atlas of genetic and epigenetic events, it now becomes feasible to assess how the patterns of mutations in a pathway influence response to drugs that are targeting such pathways. This issue is particularly important for GBM because, in contrast to other tumor types, molecularly targeted therapies have failed to alter overall survival substantially. Here, we combined functional genetic screens and comprehensive genomic analyses to identify CDK6 as a GBM oncogene that is required for proliferation and viability in a subset of GBM cell lines and tumors. Using an available small molecule targeting cyclin-dependent kinases (CDKs) 4 and 6, we sought to determine if the specific pattern of retinoblastoma pathway inactivation dictated the response to CDK4/6 inhibitor therapy. We showed that codeletion of CDKN2A and CDKN2C serves as a strong predictor of sensitivity to a selective inhibitor of CDK4/6. Thus, genome-informed drug sensitivity studies identify a subset of GBMs likely to respond to CDK4/6 inhibition. More generally, these observations demonstrate that the integration of genomic, functional and pharmacologic data can be exploited to inform the development of targeted therapy directed against specific cancer pathways.cyclin-dependent kinase inhibitor | INK4C | PD0332991 | targeted therapy C omprehensive genomic characterization of glioblastoma multiforme (GBM) has revealed major cancer-relevant pathways that are near-universally targeted for genetic or epigenetic alterations that regulate the activity of such pathways (1). Against the backdrop of an increasing appreciation for the highly heterogeneous and complex nature of the cancer genome, targeting these common pathways as a therapeutic strategy is appealing in comparison with sorting through the myriad of driver and passenger alterations for therapeutic targets that may only be relevant in a small subset of the tumors. Consistent with rapid and unrestrained proliferation that is characteristic of tumor cells, the retinoblastoma (RB) pathway is found to be nearly universally inactivated in human cancers, including glioblastoma (2). At the nexus of this pathway is the RB protein itself, the central regulator of cell cycle progression through its inhibitory effect on E2F transcription factors that in turn regulate key genes involved in proliferation. RB is tightly regulated by the opposing activating cyclindependent kinases 4 and 6 (CDK4/6) and their cyclin-D binding partners, as well as the inactivating CDK inhibitors (CKIs) such as p16 INK4A (CDKN2A) and p18 INK4C(CDKN2C) (3). Genetic alterations target...