Malignant astrocytic gliomas such as glioblastoma are the most common and lethal intracranial tumors. These cancers exhibit a relentless malignant progression characterized by widespread invasion throughout the brain, resistance to traditional and newer targeted therapeutic approaches, destruction of normal brain tissue, and certain death. The recent confluence of advances in stem cell biology, cell signaling, genome and computational science and genetic model systems have revolutionized our understanding of the mechanisms underlying the genetics, biology and clinical behavior of glioblastoma. This progress is fueling new opportunities for understanding the fundamental basis for development of this devastating disease and also novel therapies that, for the first time, portend meaningful clinical responses.Malignant gliomas are classified and subtyped on the basis of histopathological features and clinical presentation (Fig. 1). The most common and biologically aggressive of these is glioblastoma (GBM), World Health Organization (WHO) grade IV, and is defined by the hallmark features of uncontrolled cellular proliferation, diffuse infiltration, propensity for necrosis, robust angiogenesis, intense resistance to apoptosis, and rampant genomic instability. As reflected in the old moniker "multiforme," GBM presents with significant intratumoral heterogeneity on the cytopathological, transcriptional, and genomic levels. This complexity, combined with a putative cancer stem cell (CSC) subpopulation and an incomplete atlas of (epi)genetic lesions driving GBM pathogenesis, has conspired to make this cancer one of the most difficult to understand and to treat. Despite implementation of intensive therapeutic strategies and supportive care, the median survival of GBM has remained at 12 mo over the past decade.In this review, we summarize current basic and translational challenges and highlight the striking scientific advances that promise to improve the clinical course of this lethal disease. These advances include a more comprehensive view of the altered genes and pathways in glioma and how such alterations drive the hallmark pathobiological features of the disease, the identification of new molecular subtypes in GBM, an improved understanding of the cellular origins of the disease and how CSCs may influence therapeutic responses, refined model systems for use in research and preclinical experimental therapeutics, and novel therapeutic strategies for targeting keystone genetic lesions and their pathways. For reasons of length, we have not discussed the advances in such important areas as tumor immunology, the blood-brain barrier, and tumor imaging. For the first time, there is a strong sentiment that meaningful therapeutic advances will soon flow from this explosion of new molecular and biological knowledge; the remarkable technological advances in

Targeted therapies that inhibit receptor tyrosine kinases (RTKs) and the downstream phosphatidylinositol 3-kinase (PI3K) signaling pathway have shown promising anticancer activity, but their efficacy in the brain tumor glioblastoma multiforme (GBM) and other solid tumors has been modest. We hypothesized that multiple RTKs are coactivated in these tumors and that redundant inputs drive and maintain downstream signaling, thereby limiting the efficacy of therapies targeting single RTKs. Tumor cell lines, xenotransplants, and primary tumors indeed show multiple concomitantly activated RTKs. Combinations of RTK inhibitors and/or RNA interference, but not single agents, decreased signaling, cell survival, and anchorage-independent growth even in glioma cells deficient in PTEN, a frequently inactivated inhibitor of PI3K. Thus, effective GBM therapy may require combined regimens targeting multiple RTKs.

Effective clinical management of prostate cancer (PCA) has been challenged by significant intratumoural heterogeneity on the genomic and pathological levels and limited understanding of the genetic elements governing disease progression1. Here,we exploited the experimental merits of the mouse to test the hypothesis that pathways constraining progression might be activated in indolent Pten-null mouse prostate tumours and that inactivation of such progression barriers in mice would engender a metastasis-prone condition. Comparative transcriptomic and canonical pathway analyses, followed by biochemical confirmation, of normal prostate epithelium versus poorly progressive Pten-null prostate cancers revealed robust activation of the TGFβ/BMP–SMAD4 signalling axis. The functional relevance of SMAD4 was further supported by emergence of invasive, metastatic and lethal prostate cancers with 100% penetrance upon genetic deletion of Smad4 in the Pten-null mouse prostate. Pathological and molecular analysis as well as transcriptomic knowledge-based pathway profiling of emerging tumours identified cell proliferation and invasion as two cardinal tumour biological features in the metastatic Smad4/Pten-null PCA model. Follow-on pathological and functional assessment con-firmed cyclin D1 and SPP1 as key mediators of these biological processes, which together with PTEN and SMAD4, form a four-gene signature that is prognostic of prostate-specific antigen (PSA) biochemical recurrence and lethal metastasis in human PCA. This model-informed progression analysis, together with genetic, functional and translational studies, establishes SMAD4 as a key regulator of PCA progression in mice and humans.