期刊
ACTA NEUROPATHOLOGICA COMMUNICATIONS
卷 1, 期 -, 页码 -出版社
BMC
DOI: 10.1186/2051-5960-1-66
关键词
Medulloblastoma subgroups; G-protein coupled receptors; Therapeutic targets; Imaging targets
资金
- St. Baldrick's Foundation
- Alex's Lemonade Stand Foundation Pediatric Oncology Student Training program
- National Institute of Neurological Disorders and Stroke of the National Institutes of Health [T32NS007421]
- Predoctoral Training in the Pharmacological Sciences [T32GM067795]
- Children's Health Foundation Queensland
- The Brainchild Foundation (Brisbane, Australia)
- German Cancer Aid/Mildred-Scheel foundation
- NATIONAL CANCER INSTITUTE [P30CA086862] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES [T32GM007337, T32GM067795] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE [T32NS007421] Funding Source: NIH RePORTER
Background: 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. Results: 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. Conclusions: 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.
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