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

Related Links:

In conclusion, our results of bioinformatic analysis, in vitro and in vivo functional analysis suggested that REST may serve as a promoter of metastasis in pancreatic cancer. Introduction Pancreatic cancer, ranked fourth in cancer-related mortality, is characterized by its rapid progression and early metastasis (1). Patients are hardly cured by surgical resection due to the existing local invasion and distant metastasis (2). Elevating the overall survival rate for pancreatic cancer requires further elucidation of the underlying molecular mechanism of its metastasis. Epithelial-mesenchymal transition (EMT), especially...
Source: Frontiers in Oncology - Category: Cancer & Oncology Source Type: research
In conclusion, we have shown the safety and efficacy of Vemurafenib in a pediatric patient with DS affected by PXA. Ethics Statement This study was carried out in accordance with the recommendations of the Internal Review Board of the Bambino Gesù Children's Hospital with written informed consent from all subjects. All subjects gave written informed consent in accordance with the Declaration of Helsinki. The protocol was approved by the Internal Review Board of the Bambino Gesù Children's Hospital. Informed Consent The authors declare that written informed consent was obtained from the pat...
Source: Frontiers in Oncology - Category: Cancer & Oncology Source Type: research
The Hedgehog pathway is critical for the development of diverse organs. Misactivation of the Hedgehog pathway can cause developmental abnormalities and cancers, including medulloblastoma, the most common pediatric brain tumor, and basal cell carcinoma, the most common cancer in the United States. Here, we review how basic, translational, and clinical studies of the Hedgehog pathway have helped reveal how cells communicate, how intercellular communication controls development, how signaling goes awry to cause cancer, and how to use targeted molecular agents to treat both inherited and sporadic cancers.
Source: Journal of Clinical Investigation - Category: Biomedical Science Authors: Source Type: research
(Florida State University) FSU researchers identified a series of cancer-causing driver gene mutations and discovered that medulloblastoma is perhaps an even more dynamic and variable tumor than expected.
Source: EurekAlert! - Cancer - Category: Cancer & Oncology Source Type: news
Azimi Calcium signaling, in addition to its numerous physiological roles, is also implicated in several pathological conditions including cancer. An increasing body of evidence suggest critical roles of calcium signaling in the promotion of different aspects of cancer, including cell proliferation, therapy resistance and metastatic-related processes. In many cases, this is associated with altered expression and/or activity of some calcium channels and pumps. Brain cancers have also been the subject of many of these studies. In addition to diverse roles of calcium signals in normal brain function, a number of proteins i...
Source: Cancers - Category: Cancer & Oncology Authors: Tags: Review Source Type: research
We report the case of a boy, who was born to consanguineous parents. Prominently, he had multiple café-au-lait spots. At the age of 3 years he was diagnosed with a high-risk metastatic medulloblastoma. The patient died only 11 months after diagnosis of a fulminant relapse presenting as meningeal and spinal dissemination. Whole-exome sequencing of germline DNA was employed to detect the underlying mutation for this putative cancer syndrome presenting with the combination of medulloblastoma and skin alterations. After screening all possible homozygous gene SNVs, we identified a mutation ofSON, an essential p...
Source: Familial Cancer - Category: Cancer & Oncology Source Type: research
(Sanford Burnham Prebys Medical Discovery Institute) For children--whose tiny bodies are still growing--chemotherapy and radiation treatments can cause lifelong damage. Now, scientists at Sanford Burnham Prebys Medical Discovery Institute (SBP) have reported that a targeted therapy that blocks a protein called LSD1 was able to shrink tumors in mice with a form of pediatric brain cancer known as medulloblastoma. LSD1 inhibitors are currently under evaluation in clinical trials for other cancers. The study was published in Nature Communications.
Source: EurekAlert! - Biology - Category: Biology Source Type: news
CONCLUSIONS: B7-H3 CAR T cells could represent an exciting therapeutic option for patients with certain lethal relapsed or refractory pediatric malignancies which should be tested in carefully designed clinical trials. PMID: 30655315 [PubMed - as supplied by publisher]
Source: Clinical Cancer Research - Category: Cancer & Oncology Authors: Tags: Clin Cancer Res Source Type: research
ConclusionH3 K27M mutations are frequent in adult midline gliomas and have a prognostic role similar to H3 K27M wild-type high-grade tumors.
Source: Journal of Cancer Research and Clinical Oncology - Category: Cancer & Oncology Source Type: research
CONCLUSION: H3 K27M mutations are frequent in adult midline gliomas and have a prognostic role similar to H3 K27M wild-type high-grade tumors. PMID: 30610375 [PubMed - as supplied by publisher]
Source: Clin Med Res - Category: Research Authors: Tags: J Cancer Res Clin Oncol Source Type: research
More News: Biology | Brain | Brain Cancers | Brain Tumor | Cancer | Cancer & Oncology | Cancer Therapy | Environmental Health | Medulloblastoma | Neurology | Pathology | Pediatrics | Science