Medulloblastoma: Molecular Classification-Based Personal Therapeutics (original) (raw)
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The evolution of medulloblastoma therapy to personalized medicine
F1000Research, 2017
Recent advances in cancer genomics have revolutionized the characterization and classification of medulloblastomas. According to the current WHO guidelines, medulloblastomas are now classified into the following molecularly defined groups: Wnt signaling pathway (WNT)-activated, sonic hedgehog signaling pathway (SHH)-activated and tumor suppressor protein p53 (TP53)-mutant, SHH-activated and TP53-wildtype, and non-WNT/non-SHH (i.e. group 3 and group 4). Importantly, genomic, epigenomic, and proteomic advances have created a potential paradigm shift in therapeutic options. The challenge now is to (i) translate these observations into new therapeutic approaches and (ii) employ these observations in clinical practice, utilizing the classification following a molecular analysis for diagnosis and application of new subgroup-specific targeted therapeutics.
PLoS ONE, 2008
Background: Medulloblastoma is the most common malignant brain tumor in children. Despite recent improvements in cure rates, prediction of disease outcome remains a major challenge and survivors suffer from serious therapy-related sideeffects. Recent data showed that patients with WNT-activated tumors have a favorable prognosis, suggesting that these patients could be treated less intensively, thereby reducing the side-effects. This illustrates the potential benefits of a robust classification of medulloblastoma patients and a detailed knowledge of associated biological mechanisms.
Genomics Identifies Medulloblastoma Subgroups That Are Enriched for Specific Genetic Alterations
Journal of Clinical Oncology, 2006
Purpose Traditional genetic approaches to identify gene mutations in cancer are expensive and laborious. Nonetheless, if we are to avoid rejecting effective molecular targeted therapies, we must test these drugs in patients whose tumors harbor mutations in the drug target. We hypothesized that gene expression profiling might be a more rapid and cost-effective method of identifying tumors that contain specific genetic abnormalities. Materials and Methods Gene expression profiles of 46 samples of medulloblastoma were generated using the U133av2 Affymetrix oligonucleotide array and validated using real-time reverse transcriptase polymerase chain reaction (RT-PCR) and immunohistochemistry. Genetic abnormalities were confirmed using fluorescence in situ hybridization (FISH) and direct sequencing. Results Unsupervised analysis of gene expression profiles partitioned medulloblastomas into five distinct subgroups (subgroups A to E). Gene expression signatures that distinguished these subgro...
Cancer and Metastasis Reviews, 2020
Medulloblastoma (MB) is the most common malignant childhood tumor of the brain. Multimodal treatment consisting of surgery, radiation therapy, and chemotherapy reduced cumulative incidence of late mortality but increased the incidence of subsequent neoplasms and severe, incapacitating chronic health conditions. Present treatment strategies fail to recognize heterogeneity within patients despite wide divergence in individual responses. The persistent mortality rates and serious side effects of non-targeted cytotoxic therapies indicate a need for more refined therapeutic approaches. Advanced genomic research has led to the accumulation of an enormous amount of genetic information and resulted in a consensus distinguishing four molecular subgroups, WNT-activated, SHH-activated, and Group 3 and 4 medulloblastomas. These have distinct origin, demographics, molecular alterations, and clinical outcomes. Although subgroup affiliation does not predict response to therapy, new subgroup-specif...
New perspectives in the treatment of adult medulloblastoma in the era of molecular oncology
Critical Reviews in Oncology/Hematology, 2015
Medulloblastoma is the most common central nervous system tumor in children, while it is extremely rare in adults. Multimodal treatment involving surgery, radiotherapy and chemotherapy can improve the prognosis of this disease, and recent advances in molecular biology have allowed the identification of molecular subgroups (WNT, SHH, Groups 3 and 4), each of which have different cytogenetic, mutational and gene expression signatures, demographics, histology and prognosis. The present review focuses on the state of the art for adult medulloblastoma treatment and on novel molecular advances and their future implications in the treatment of this disease.
Functional Precision Medicine Identifies New Therapeutic Candidates for Medulloblastoma
Cancer Research, 2020
Medulloblastoma is among the most common malignant brain tumors in children. Recent studies have identified at least four subgroups of the disease that differ in terms of molecular characteristics and patient outcomes. Despite this heterogeneity, most patients with medulloblastoma receive similar therapies, including surgery, radiation, and intensive chemotherapy. Although these treatments prolong survival, many patients still die from the disease and survivors suffer severe long-term side effects from therapy. We hypothesize that each patient with medulloblastoma is sensitive to different therapies and that tailoring therapy based on the molecular and cellular characteristics of patients' tumors will improve outcomes. To test this, we assembled a panel of orthotopic patient-derived xenografts (PDX) and subjected them to DNA sequencing, gene expression profiling, and high-throughput drug screening. Analysis of DNA sequencing revealed that most medulloblastomas do not have action...
Molecular Targeted Therapies: Time for a Paradigm Shift in Medulloblastoma Treatment?
Cancers, 2022
Medulloblastoma is a rare malignancy of the posterior cranial fossa. Although until now considered a single disease, according to the current WHO classification, it is a heterogeneous tumor that comprises multiple molecularly defined subgroups, with distinct gene expression profiles, pathogenetic driver alterations, clinical behaviors and age at onset. Adult medulloblastoma, in particular, is considered a rarer “orphan” entity in neuro-oncology practice because while treatments have progressively evolved for the pediatric population, no practice-changing prospective, randomized clinical trials have been performed in adults. In this scenario, the toughest challenge is to transfer the advances in cancer genomics into new molecularly targeted therapeutics, to improve the prognosis of this neoplasm and the treatment-related toxicities. Herein, we focus on the recent advances in targeted therapy of medulloblastoma based on the new and deeper knowledge of disease biology.
Classifying Medulloblastoma Subgroups Based on Small, Clinically Achievable Gene Sets
Frontiers in Oncology
As treatment protocols for medulloblastoma (MB) are becoming subgroup-specific, means for reliably distinguishing between its subgroups are a timely need. Currently available methods include immunohistochemical stains, which are subjective and often inconclusive, and molecular techniques—e.g., NanoString, microarrays, or DNA methylation assays—which are time-consuming, expensive and not widely available. Quantitative PCR (qPCR) provides a good alternative for these methods, but the current NanoString panel which includes 22 genes is impractical for qPCR. Here, we applied machine-learning–based classifiers to extract reliable, concise gene sets for distinguishing between the four MB subgroups, and we compared the accuracy of these gene sets to that of the known NanoString 22-gene set. We validated our results using an independent microarray-based dataset of 92 samples of all four subgroups. In addition, we performed a qPCR validation on a cohort of 18 patients diagnosed with SHH, Gro...