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

Akt/protein kinase B critically regulates the balance between cell survival and apoptosis. Phosphorylation of Akt at two key sites, the activation loop and the hydrophobic motif, activates the kinase and promotes cell survival. The mechanism of dephosphorylation and signal termination is unknown. Here, we identify a protein phosphatase, PH domain leucine-rich repeat protein phosphatase (PHLPP), that specifically dephosphorylates the hydrophobic motif of Akt (Ser473 in Akt1), triggering apoptosis and suppressing tumor growth. The effects of PHLPP on apoptosis are prevented in cells expressing an S473D construct of Akt, revealing that the hydrophobic motif is the primary cellular target of PHLPP. PHLPP levels are markedly reduced in several colon cancer and glioblastoma cell lines that have elevated Akt phosphorylation. Reintroduction of PHLPP into a glioblastoma cell line causes a dramatic suppression of tumor growth. These data are consistent with PHLPP terminating Akt signaling by directly dephosphorylating and inactivating Akt.

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Human cells have twenty-three pairs of chromosomes but in cancer, genes can be amplified in chromosomes or in circular extrachromosomal DNA (ECDNA), whose frequency and functional significance are not understood1–4. We performed whole genome sequencing, structural modeling and cytogenetic analyses of 17 different cancer types, including 2572 metaphases, and developed ECdetect to conduct unbiased integrated ECDNA detection and analysis. ECDNA was found in nearly half of human cancers varying by tumor type, but almost never in normal cells. Driver oncogenes were amplified most commonly on ECDNA, elevating transcript level. Mathematical modeling predicted that ECDNA amplification elevates oncogene copy number and increases intratumoral heterogeneity more effectively than chromosomal amplification, which we validated by quantitative analyses of cancer samples. These results suggest that ECDNA contributes to accelerated evolution in cancer.

Boundless Bio, Inc. (BB), and serve as consultants. V.B. is a co-founder, and has equity interest in Boundless Bio, inc. (BB) and Digital Proteomics, LLC (DP), and receives income from DP. The terms of this arrangement have been reviewed and approved by the University of California, San Diego in accordance with its conflict of interest policies. BB and DP were not involved in the research presented here. Data Availability. Whole genome-, RNA-, ATAC-, MNase-, ChIP-, PLAC-Seq data are deposited in the NCBI Sequence Read Archive (BioProject: PRJNA506071). The source data files of the pixel quantification of ATAC-see on metaphase chromosome spread images to create Extended Data Figure 7d are available on Figshare (