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  • 1
    Language: English
    In: Acta neuropathologica communications, 10 October 2013, Vol.1, pp.66
    Description: Medulloblastoma is the most common malignant brain tumor in children. Genetic profiling has identified four principle tumor subgroups; each subgroup is characterized by different initiating mutations, genetic and clinical profiles, and prognoses. The two most well-defined subgroups are caused by overactive signaling in the WNT and SHH mitogenic pathways; less is understood about Groups 3 and 4 medulloblastoma. Identification of tumor subgroup using molecular classification is set to become an important component of medulloblastoma diagnosis and staging, and will likely guide therapeutic options. However, thus far, few druggable targets have emerged. G-protein coupled receptors (GPCRs) possess characteristics that make them ideal targets for molecular imaging and therapeutics; drugs targeting GPCRs account for 30-40% of all current pharmaceuticals. While expression patterns of many proteins in human medulloblastoma subgroups have been discerned, the expression pattern of GPCRs in medulloblastoma has not been investigated. We hypothesized that analysis of GPCR expression would identify clear subsets of medulloblastoma and suggest distinct GPCRs that might serve as molecular targets for both imaging and therapy. Our study found that medulloblastoma tumors fall into distinct clusters based solely on GPCR expression patterns. Normal cerebellum clustered separately from the tumor samples. Further, two of the tumor clusters correspond with high fidelity to the WNT and SHH subgroups of medulloblastoma. Distinct over-expressed GPCRs emerge; for example, LGR5 and GPR64 are significantly and uniquely over-expressed in the WNT subgroup of tumors, while PTGER4 is over-expressed in the SHH subgroup. Uniquely under-expressed GPCRs were also observed. Our key findings were independently validated using a large international dataset. Our results identify GPCRs with potential to act as imaging and therapeutic targets. Elucidating tumorigenic pathways is a secondary benefit to identifying differential GPCR expression patterns in medulloblastoma tumors.
    Keywords: Cerebellar Neoplasms -- Classification ; Cerebellum -- Metabolism ; Medulloblastoma -- Classification ; Receptors, G-Protein-Coupled -- Metabolism
    E-ISSN: 2051-5960
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  • 2
    Language: English
    In: Acta neuropathologica communications, 24 January 2014, Vol.2, pp.10
    Description: Medulloblastoma is the most common intracranial childhood malignancy and a genetically heterogeneous disease. Despite recent advances, current therapeutic approaches are still associated with high morbidity and mortality. Recent molecular profiling has suggested the stratification of medulloblastoma from one single disease into four distinct subgroups namely: WNT Group (best prognosis), SHH Group (intermediate prognosis), Group 3 (worst prognosis) and Group 4 (intermediate prognosis). BMI1 is a Polycomb group repressor complex gene overexpressed across medulloblastoma subgroups but most significantly in Group 4 tumours. Bone morphogenetic proteins are morphogens belonging to TGF-β superfamily of growth factors, known to inhibit medulloblastoma cell proliferation and induce apoptosis. Here we demonstrate that human medulloblastoma of Group 4 characterised by the greatest overexpression of BMI1, also display deregulation of cell adhesion molecules. We show that BMI1 controls intraparenchymal invasion in a novel xenograft model of human MB of Group 4, while in vitro assays highlight that cell adhesion and motility are controlled by BMI1 in a BMP dependent manner. BMI1 controls MB cell migration and invasion through repression of the BMP pathway, raising the possibility that BMI1 could be used as a biomarker to identify groups of patients who may benefit from a treatment with BMP agonists.
    Keywords: Bone Morphogenetic Proteins -- Metabolism ; Cell Adhesion -- Physiology ; Cerebellar Neoplasms -- Genetics ; Medulloblastoma -- Genetics ; Polycomb Repressive Complex 1 -- Genetics
    E-ISSN: 2051-5960
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  • 3
    Language: English
    In: Acta neuropathologica communications, 2014, Vol. 2
    Description: TP53 mutations confer subgroup specific poor survival for children with medulloblastoma. We hypothesized that WNT activation which is associated with improved survival for such children abrogates TP53 related radioresistance and can be used to sensitize TP53 mutant tumors for radiation. We examined the subgroup-specific role of TP53 mutations in a cohort of 314 patients treated with radiation. TP53 wild-type or mutant human medulloblastoma cell-lines and normal neural stem cells were used to test radioresistance of TP53 mutations and the radiosensitizing effect of WNT activation on tumors and the developing brain. Children with WNT/TP53 mutant medulloblastoma had higher 5-year survival than those with SHH/TP53 mutant tumours (100% and 36.6%±8.7%, respectively (p〈0.001)). Introduction of TP53 mutation into medulloblastoma cells induced radioresistance (survival fractions at 2Gy (SF2) of 89%±2% vs. 57.4%±1.8% (p〈0.01)). In contrast, beta-catenin mutation sensitized TP53 mutant cells to radiation (p〈0.05). Lithium, an activator of the WNT pathway, sensitized TP53 mutant medulloblastoma to radiation (SF2 of 43.5%±1.5% in lithium treated cells vs. 56.6±3% (p〈0.01)) accompanied by increased number of gammaH2AX foci. Normal neural stem cells were protected from lithium induced radiation damage (SF2 of 33%±8% for lithium treated cells vs. 27%±3% for untreated controls (p=0.05). Poor survival of patients with TP53 mutant medulloblastoma may be related to radiation resistance. Since constitutive activation of the WNT pathway by lithium sensitizes TP53 mutant medulloblastoma cells and protect normal neural stem cells from radiation, this oral drug may represent an attractive novel therapy for high-risk medulloblastomas.
    Keywords: Medical And Health Sciences ; Clinical Medicine ; Cancer And Oncology ; Medicin Och Hälsovetenskap ; Klinisk Medicin ; Cancer Och Onkologi
    ISSN: 2051-5960
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