Developmental phosphoproteomics identifies the kinase CK2 as a driver of Hedgehog signaling and a therapeutic target in medulloblastoma

A major limitation of targeted cancer therapy is the rapid emergence of drug resistance, which often arises through mutations at or downstream of the drug target or through intrinsic resistance of subpopulations of tumor cells. Medulloblastoma (MB), the most common pediatric brain tumor, is no exception, and MBs that are driven by sonic hedgehog (SHH) signaling are particularly aggressive and drug-resistant. To find new drug targets and therapeutics for MB that may be less susceptible to common resistance mechanisms, we used a developmental phosphoproteomics approach in murine granule neuron precursors (GNPs), the developmental cell of origin of MB. The protein kinase CK2 emerged as a driver of hundreds of phosphorylation events during the proliferative, MB-like stage of GNP growth, including the phosphorylation of three of the eight proteins commonly amplified in MB. CK2 was critical to the stabilization and activity of the transcription factor GLI2, a late downstream effector in SHH signaling. CK2 inhibitors decreased the viability of primary SHH-type MB patient cells in culture and blocked the growth of murine MB tumors that were resistant to currently available Hh inhibitors, thereby extending the survival of tumor-bearing mice. Because of structural interactions, one CK2 inhibitor (CX-4945) inhibited both wild-type and mutant CK2, indicating that this drug may avoid at least one common mode of acquired resistance. These findings suggest that CK2 inhibitors may be effecti...
Source: Signal Transduction Knowledge Environment - Category: Science Authors: Tags: STKE Research Articles Source Type: news

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The objective of this study is to investigate the involvement of somatic driver gene mutations in these medulloblastoma subgroups. We obtained medulloblastoma data from the Catalogue of Somatic Mutations in Cancer (COSMIC), which contains distinct samples that were not previously studied in a large cohort. We identified somatic driver gene mutations and the signaling pathways affected by these driver genes for medulloblastoma subgroups using bioinformatics tools. We have revealed novel infrequent drivers in these subgroups that contribute to our understanding of tumor heterogeneity in medulloblastoma. Normally SHH signalin...
Source: Journal of Cancer - Category: Cancer & Oncology Authors: Tags: Research Paper Source Type: research
Medulloblastoma (MB) is the most common malignant brain tumor of childhood. Although outcomes have improved in recent decades, new treatments are still needed to improve survival and reduce treatment-related complications. The MB subtypes groups 3 and 4 represent a particular challenge due to their intragroup heterogeneity, which limits the options for "rational" targeted therapies. Here, we report a systems biology approach to drug repositioning that integrates a nonparametric, bootstrapping-based simulated annealing algorithm and a 3D drug functional network to characterize dysregulated driver signaling network...
Source: Science Translational Medicine - Category: Biomedical Science Authors: Tags: Research Articles Source Type: research
Abstract Utilization of human embryonic stem cells (hESCs) as a model system to study highly malignant pediatric cancers has led to significant insight into the molecular mechanisms governing tumor progression and has revealed novel therapeutic targets for these devastating diseases. Here, we describe a method for generating heterogeneous populations of neural precursors from both normal and neoplastic hESCs and the subsequent injection of neoplastic human embryonic neural cells (hENs) into intracerebellar or intracranial xenograft models. Histopathologically, neural tumors derived from neoplastic hENs exhibit fea...
Source: Mol Biol Cell - Category: Molecular Biology Authors: Tags: Methods Mol Biol Source Type: research
CONCLUSION: Our results suggest that the small molecule inhibitors of STAT3 upstream kinases, ruxolitinib, tofactinib, KX2-391, and dasatinib could be novel and attractive candidate drugs for the treatments of human medulloblastoma. PMID: 30332965 [PubMed - as supplied by publisher]
Source: Current Cancer Drug Targets - Category: Cancer & Oncology Authors: Tags: Curr Cancer Drug Targets Source Type: research
(Huntsman Cancer Institute) New research published in Nature Communications from scientists at Huntsman Cancer Institute (HCI) at the University of Utah (U of U), in collaboration with the Stanford University School of Medicine, shows a specific protein regulates both the initiation of cancer spreading and the self-renewal of cancer cells in medulloblastoma, a type of pediatric brain cancer.
Source: EurekAlert! - Cancer - Category: Cancer & Oncology Source Type: news
Publication date: 10 September 2018Source: Cancer Cell, Volume 34, Issue 3Author(s): Tenley C. Archer, Tobias Ehrenberger, Filip Mundt, Maxwell P. Gold, Karsten Krug, Clarence K. Mah, Elizabeth L. Mahoney, Colin J. Daniel, Alexander LeNail, Divya Ramamoorthy, Philipp Mertins, D.R. Mani, Hailei Zhang, Michael A. Gillette, Karl Clauser, Michael Noble, Lauren C. Tang, Jessica Pierre-François, Jacob Silterra, James JensenSummaryThere is a pressing need to identify therapeutic targets in tumors with low mutation rates such as the malignant pediatric brain tumor medulloblastoma. To address this challenge, we quantitativel...
Source: Cancer Cell - Category: Cancer & Oncology Source Type: research
MT, Elias JE, Scott MP Abstract A major limitation of targeted cancer therapy is the rapid emergence of drug resistance, which often arises through mutations at or downstream of the drug target or through intrinsic resistance of subpopulations of tumor cells. Medulloblastoma (MB), the most common pediatric brain tumor, is no exception, and MBs that are driven by sonic hedgehog (SHH) signaling are particularly aggressive and drug-resistant. To find new drug targets and therapeutics for MB that may be less susceptible to common resistance mechanisms, we used a developmental phosphoproteomics approach in murine granu...
Source: Science Signaling - Category: Biomedical Science Authors: Tags: Sci Signal Source Type: research
Investigators at the NCI Laboratory of Immune Cell Biology  discovered an Anti-TNF Induced Apoptosis (ATIA) protein, which protects cells against apoptosis.  ATIA is highly expressed in glioblastoma and astrocytomas and its inhibition results in increased cell sensitivity to TNF-related apoptosis-inducing ligand induced cell death.  Hence, ATIA assays ma y enable clinicians to effectively stratify patients for appropriate treatment.  ATIA exists in a soluble form that can be detected in culture medium of ATIA expressing cells indicating it could be used to develop a non-invasive, blood based diagnostic ...
Source: NIH OTT Licensing Opportunities - Category: Research Authors: Source Type: research
Publication date: 10 July 2018Source: Cell Reports, Volume 24, Issue 2Author(s): Seçkin Akgül, Yinghua Li, Siyuan Zheng, Marcel Kool, Daniel M. Treisman, Chaoyang Li, Yuan Wang, Susanne Gröbner, Tsuneo Ikenoue, Yiping Shen, Sandra Camelo-Piragua, Gerald Tomasek, Sebastian Stark, Vinay Guduguntla, James F. Gusella, Kun-Liang Guan, Stefan M. Pfister, Roel G.W. Verhaak, Yuan ZhuSummaryMost human cancers arise from stem and progenitor cells by the sequential accumulation of genetic and epigenetic alterations, while cancer modeling typically requires simultaneous multiple oncogenic events. Here, we show that a ...
Source: Cell Reports - Category: Cytology Source Type: research
Brain tumors are the most common solid tumor among children under 15, representing 20% of childhood cancers. Prognosis and therapeutic options vary dramatically based on histologic and molecular profiles. We have studied 222 brain tumors using the CHOP Comprehensive Solid Tumor Panel, which interrogates 238 cancer genes and 110 fusion partners. The most common tumors are pilocytic/pilomyxoid astrocytoma (67), medulloblastoma (23) and diffuse midline glioma (17). Clinically significant genomic alterations were identified in 93% of patients.
Source: Cancer Genetics and Cytogenetics - Category: Genetics & Stem Cells Authors: Source Type: research
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