Temporal profiling of therapy resistance in human medulloblastoma identifies novel targetable drivers of recurrence (original) (raw)
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Journal of Health and Rehabilitation Research, 2024
Background: Medulloblastoma (MB), a leading intracranial malignant tumor in children, presents complex challenges due to its diverse molecular pathways and resistance to traditional therapies. Recent research has provided insights into its pathogenesis, revealing significant genetic aberrations and molecular subgroups that influence disease progression and treatment response. Objective: This review aims to synthesize current knowledge about the molecular mechanisms underlying MB's pathogenesis, therapeutic resistance, and to evaluate the potential and efficacy of emerging treatment strategies. Methods: A comprehensive literature review was conducted, focusing on studies published in major scientific databases. The criteria for inclusion involved relevance to MB's molecular pathways, epidemiology, treatment strategies, and therapeutic resistance. Key data were extracted and analyzed systematically to understand the disease's molecular underpinnings and treatment implications. Results: MB is classified into four molecular subgroups-WNT, SHH, Group 3, and Group 4-each with distinct genetic mutations and clinical presentations. Key findings include the identification of specific signaling pathways crucial for tumor growth and survival, such as Wnt, PI3K/Akt/mTOR, and Hedgehog. Treatments are evolving towards targeted therapies, including immunotherapies and drugs focusing on specific signaling pathways. Diagnostic approaches primarily rely on imaging techniques like CT and MRI, which help in identifying tumor characteristics essential for treatment planning. Conclusion: Advancements in molecular biology have significantly enhanced the understanding of MB, leading to more personalized and targeted treatment approaches. These developments promise to improve survival rates and reduce treatment-related morbidity, thereby improving the quality of life for MB patients. However, ongoing research and innovation remain crucial to address the challenges in treating this complex disease.
Rethinking medulloblastoma from a targeted therapeutics perspective
Journal of neuro-oncology, 2018
Medulloblastoma is an aggressive but potentially curable central nervous system tumor that remains a treatment challenge. Analysis of therapeutic targets can provide opportunities for the selection of agents. Using multiplatform analysis, 36 medulloblastomas were extensively profiled from 2009 to 2015. Immunohistochemistry, next generation sequencing, chromogenic in situ hybridization, and fluorescence in situ hybridization were used to identify overexpressed proteins, immune checkpoint expression, mutations, tumor mutational load, and gene amplifications. High expression of MRP1 (89%, 8/9 tumors), TUBB3 (86%, 18/21 tumors), PTEN (85%, 28/33 tumors), TOP2A (84%, 26/31 tumors), thymidylate synthase (TS; 80%, 24/30 tumors), RRM1 (71%, 15/21 tumors), and TOP1 (63%, 19/30 tumors) were found in medulloblastoma. TOP1 was found to be enriched in metastatic tumors (90%; 9/10) relative to posterior fossa cases (50%; 10/20) (p = 0.0485, Fisher exact test), and there was a positive correlation...
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...
MODL-20. Metabolic rewiring support the onset of chemotherapy resistance in medulloblastoma
Neuro-Oncology
Medulloblastoma (MB) is the deadliest brain tumor of childhood, intrinsically characterized by fast growth, high invasiveness, and resistance to treatments. With the aim to deepen the molecular basis of MB aggressiveness and recurrence, we established an in vitro model of MB resistance to chemotherapy, in which, a weekly exposure to a cocktail of chemotherapeutics commonly used in MB treatment (Vincristine, Etoposide, Cisplatin, Cyclophosphamide – VECC) induces the selection of cells that progressively acquire resistance to subsequent VECC treatments. Preliminary data on our model of MB resistance show that resistant cells induce the activation of the two main regulator of pentose phosphate pathway TKT and G6PD via the activation of Nrf2 transcriptional activity. Moreover, resistant cells show an increase in hypoxia inducible factor-1α (HIF-1α) together with an augmented expression of glycolytic enzymes HK1, PFKB-3, PDK1 and LDHA and increased glycolytic capacity. Interestingly, enr...
Emergence and maintenance of actionable genetic drivers at medulloblastoma relapse
Neuro-Oncology, 2021
Background Less than 5% of medulloblastoma (MB) patients survive following failure of contemporary radiation-based therapies. Understanding the molecular drivers of medulloblastoma relapse (rMB) will be essential to improve outcomes. Initial genome-wide investigations have suggested significant genetic divergence of the relapsed disease. Methods We undertook large-scale integrated characterization of the molecular features of rMB—molecular subgroup, novel subtypes, copy number variation (CNV), and driver gene mutation. 119 rMBs were assessed in comparison with their paired diagnostic samples (n = 107), alongside an independent reference cohort sampled at diagnosis (n = 282). rMB events were investigated for association with outcome post-relapse in clinically annotated patients (n = 54). Results Significant genetic evolution occurred over disease-course; 40% of putative rMB drivers emerged at relapse and differed significantly between molecular subgroups. Non-infant MBSHH displayed s...
BMI1 is a therapeutic target in recurrent medulloblastoma
Oncogene, 2018
Medulloblastoma (MB) is the most frequent malignant pediatric brain tumor, representing 20% of newly diagnosed childhood central nervous system malignancies. Although advances in multimodal therapy yielded a 5-year survivorship of 80%, MB still accounts for the leading cause of childhood cancer mortality. In this work, we describe the epigenetic regulator BMI1 as a novel therapeutic target for the treatment of recurrent human Group 3 MB, a childhood brain tumor for which there is virtually no treatment option beyond palliation. Current clinical trials for recurrent MB patients based on genomic profiles of primary, treatment-naive tumors will provide limited clinical benefit since recurrent metastatic MBs are highly genetically divergent from their primary tumor. Using a small molecule inhibitor against BMI1, PTC-028, we were able to demonstrate complete ablation of self-renewal of MB stem cells in vitro. When administered to mice xenografted with patient tumors, we observed signific...
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.
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...
The rationale for targeted therapies in medulloblastoma
2014
Medulloblastoma (MB) is the most frequent malignant brain tumor in children. Patients with MB who are classified as having high-risk disease or those with recurrent disease respond poorly to current therapies and have an increased risk of MB-related mortality. Preclinical studies and molecular profiling of MB tumors have revealed upregulation or activation of several key signaling pathways such as the sonic hedgehog and WNTpathways. Although the exact mechanisms underlying MB tumorigenesis remain poorly understood, inhibiting these key pathways with molecularly targeted therapies represents an important approach to improving MB outcomes. Several molecularly targeted therapies are already under clinical investigation in MB patients. We discuss current preclinical and clinical data, as well as data from clinical trials of targeted therapies that are either ongoing or in development for MB.