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Molecular Oncology Mar 2023Selective targeting of N-Myc-driven Sonic hedgehog (SHH) medulloblastoma has been a challenge for many years and, despite decades of research, few targeted therapy...
Selective targeting of N-Myc-driven Sonic hedgehog (SHH) medulloblastoma has been a challenge for many years and, despite decades of research, few targeted therapy opportunities exist. Recently, Kuzuoglu-Ozturk et al. characterized the translatome of N-Myc-driven medulloblastoma as a promising therapeutic target. The study showed that N-Myc controls a subset of members of the protein folding machinery that could be inhibited pharmacologically and validated a subset of Hsp70 functions as required for medulloblastoma progression in vitro and in vivo.
Topics: Humans; Cerebellar Neoplasms; Hedgehog Proteins; Medulloblastoma; Protein Folding; Signal Transduction; N-Myc Proto-Oncogene Protein
PubMed: 36786675
DOI: 10.1002/1878-0261.13395 -
International Journal of Molecular... May 2021Medulloblastoma (MB) is one of the most frequent and malignant brain tumors in children. The prognosis depends on the advancement of the disease and the patient's age.... (Review)
Review
Medulloblastoma (MB) is one of the most frequent and malignant brain tumors in children. The prognosis depends on the advancement of the disease and the patient's age. Current therapies, which include surgery, chemotherapy, and irradiation, despite being quite effective, cause significant side effects that influence the central nervous system's function and cause neurocognitive deficits. Therefore, they substantially lower the quality of life, which is especially severe in a developing organism. Thus, there is a need for new therapies that are less toxic and even more effective. Recently, knowledge about the epigenetic mechanisms that are responsible for medulloblastoma development has increased. Epigenetics is a phenomenon that influences gene expression but can be easily modified by external factors. The best known epigenetic mechanisms are histone modifications, DNA methylation, or noncoding RNAs actions. Epigenetic mechanisms comprehensively explain the complex phenomena of carcinogenesis. At the same time, they seem to be a potential key to treating medulloblastoma with fewer complications than past therapies. This review presents the currently known epigenetic mechanisms that are involved in medulloblastoma pathogenesis and the potential therapies that use epigenetic traits to cure medulloblastoma while maintaining a good quality of life and ensuring a higher median overall survival rate.
Topics: Cerebellar Neoplasms; Epigenesis, Genetic; Gene Expression Regulation, Neoplastic; Humans; Medulloblastoma; MicroRNAs; RNA, Long Noncoding
PubMed: 34066495
DOI: 10.3390/ijms22094925 -
Neurotherapeutics : the Journal of the... Oct 2022Critical discoveries over the past two decades have transformed our understanding of medulloblastoma from a single entity into a clinically and biologically... (Review)
Review
Critical discoveries over the past two decades have transformed our understanding of medulloblastoma from a single entity into a clinically and biologically heterogeneous disease composed of at least four molecularly distinct subgroups with prognostically and therapeutically relevant genomic signatures. Contemporary clinical trials also have provided valuable insight guiding appropriate treatment strategies. Despite therapeutic and biological advances, medulloblastoma patients across the age spectrum experience tumor- and treatment-related morbidity and mortality. Using an updated risk stratification approach integrating both clinical and molecular features, ongoing research seeks to (1) cautiously reduce therapy and mitigate toxicity in low-average risk patients, and (2) thoughtfully intensify treatment with incorporation of novel, biologically guided agents for patients with high-risk disease. Herein, we review important historical and contemporary studies, discuss management updates, and summarize current knowledge of the biological landscape across unique pediatric, infant, young adult, and relapsed medulloblastoma populations.
Topics: Infant; Humans; Child; Medulloblastoma; Brain Neoplasms; Genomics; Cerebellar Neoplasms
PubMed: 35859223
DOI: 10.1007/s13311-022-01273-0 -
Indian Journal of Pathology &... May 2022Embryonal tumors are a heterogenous group of neoplasms mostly defined by recurrent genetic driver events. They have been, previously, broadly classified as either... (Review)
Review
Embryonal tumors are a heterogenous group of neoplasms mostly defined by recurrent genetic driver events. They have been, previously, broadly classified as either medulloblastoma or supratentorial primitive neuroectodermal tumors (PNETs). However, the application of DNA methylation/gene expression profiling in large series of neoplasms histologically defined as PNET, revealed tumors, which showed genetic events associated with glial tumors. These findings led to the definitive removal of the term "PNET" in the 2016 World Health Organization (WHO) classification of CNS tumors. Moreover, further studies on a large scale of methylation profiling have allowed the identification of new molecular-defined entities and have largely influenced the 5 edition of the WHO classification of CNS tumors (WHO CNS5) for both medulloblastomas and other CNS embryonal tumors. The importance of molecular characteristics in CNS embryonal tumors is well represented by the identification of different molecular groups and subgroups in medulloblastoma. So, in the CNS5, the emerged group 3 and group 4 belong to the classification, and the four molecular and morphologic types are now combined into a unique section. Among other embryonal tumors, two new recognized entities are introduced in CNS5: CNS neuroblastoma, FOXR2-activated, and CNS tumor with BCOR internal tandem duplication (ITD). Embryonal tumor with multilayered rosettes (ETMR), already present in the previous classification now has a revised nomenclature as a result of the new DICER1 alteration, additional to the formerly known C19MC. Regarding atypical teratoid/rhabdoid tumor (AT/RT), three molecular subgroups are recognized in CNS5. The combination of histopathological and molecular features reflects the complexity of all these tumors and gives critical information in terms of prognosis and therapy. This encourages the use of a layered diagnostic report with the integrated diagnosis at the top, succeeded by layers including the histological, molecular, and other essential details.
Topics: Brain Neoplasms; Central Nervous System Neoplasms; Cerebellar Neoplasms; DEAD-box RNA Helicases; Forkhead Transcription Factors; Humans; Medulloblastoma; Neoplasms, Germ Cell and Embryonal; Neuroectodermal Tumors, Primitive; Ribonuclease III; World Health Organization
PubMed: 35562137
DOI: 10.4103/ijpm.ijpm_1049_21 -
International Journal of Molecular... Jun 2018Mechanistic target of rapamycin (mTOR) is a master signaling pathway that regulates organismal growth and homeostasis, because of its implication in protein and lipid... (Review)
Review
Mechanistic target of rapamycin (mTOR) is a master signaling pathway that regulates organismal growth and homeostasis, because of its implication in protein and lipid synthesis, and in the control of the cell cycle and the cellular metabolism. Moreover, it is necessary in cerebellar development and stem cell pluripotency maintenance. Its deregulation has been implicated in the medulloblastoma and in medulloblastoma stem cells (MBSCs). Medulloblastoma is the most common malignant solid tumor in childhood. The current therapies have improved the overall survival but they carry serious side effects, such as permanent neurological sequelae and disability. Recent studies have given rise to a new molecular classification of the subgroups of medulloblastoma, specifying 12 different subtypes containing novel potential therapeutic targets. In this review we propose the targeting of mTOR, in combination with current therapies, as a promising novel therapeutic approach.
Topics: Animals; Bridged Bicyclo Compounds, Heterocyclic; Cerebellar Neoplasms; Humans; Medulloblastoma; Molecular Targeted Therapy; Morpholines; Protein Kinase Inhibitors; Pyrimidines; Signal Transduction; TOR Serine-Threonine Kinases; Triazines
PubMed: 29932116
DOI: 10.3390/ijms19071838 -
Journal of Medical Case Reports Aug 2022Medulloblastoma is a malignant brain tumor that is common in children but very uncommon in adults, especially those older than 40 years, accounting for less than 1% of...
BACKGROUND
Medulloblastoma is a malignant brain tumor that is common in children but very uncommon in adults, especially those older than 40 years, accounting for less than 1% of all primary brain tumors in adults. Although surgery and radiotherapy play an important role treatment of adult medulloblastoma, the use of chemotherapy is controversial. This is the first instance of adult medulloblastoma at the Ocean Road Cancer Institute in Tanzania.
CASE DESCRIPTION
We report the case of a 51-year-old female of African ethnicity who was diagnosed with high-risk hemispheric posterior cranial fossa medulloblastoma of classic type with World Health Organization central nervous system grade 4 and Chang stage M0. Immunohistochemistry, reticulin stain, and molecular subtyping could not be done because they were not available. She was treated by subtotal posterior cranial fossa tumor resection followed by adjuvant concurrent chemo-craniospinal radiation and adjuvant chemotherapy.
CONCLUSION
Even in adults over 50 years old, medulloblastoma should be included in the differential diagnosis of posterior fossa tumor. Adult medulloblastoma is a very rare and very heterogeneous tumor, but it has a good prognosis. Immunohistochemistry and molecular subclustering are difficult to implement in low-income countries such as Tanzania owing to cost. Treatment of adult medulloblastoma is highly heterogeneous among (and even within) facilities. There is no evidence that the extent of resection enhances survival. While craniospinal radiation therapy improves survival, there is controversy about the role of chemotherapy in managing adult MB.
Topics: Adult; Brain Neoplasms; Cerebellar Neoplasms; Chemotherapy, Adjuvant; Child; Combined Modality Therapy; Female; Humans; Medulloblastoma; Middle Aged
PubMed: 36002876
DOI: 10.1186/s13256-022-03531-3 -
Neoplasia (New York, N.Y.) May 2023Leptomeningeal disease (LMD) in pediatric brain tumors (PBTs) is a poorly understood and categorized phenomenon. LMD incidence rates, as well as diagnosis, treatment,...
Leptomeningeal disease (LMD) in pediatric brain tumors (PBTs) is a poorly understood and categorized phenomenon. LMD incidence rates, as well as diagnosis, treatment, and screening practices, vary greatly depending on the primary tumor pathology. While LMD is encountered most frequently in medulloblastoma, reports of LMD have been described across a wide variety of PBT pathologies. LMD may be diagnosed simultaneously with the primary tumor, at time of recurrence, or as primary LMD without a primary intraparenchymal lesion. Dissemination and seeding of the cerebrospinal fluid (CSF) involves a modified invasion-metastasis cascade and is often the result of direct deposition of tumor cells into the CSF. Cells develop select environmental advantages to survive the harsh, nutrient poor and turbulent environment of the CSF and leptomeninges. Improved understanding of the molecular mechanisms that underlie LMD, along with improved diagnostic and treatment approaches, will help the prognosis of children affected by primary brain tumors.
Topics: Child; Humans; Meningeal Neoplasms; Brain Neoplasms; Medulloblastoma; Prognosis; Cerebellar Neoplasms
PubMed: 37011459
DOI: 10.1016/j.neo.2023.100898 -
Cancer Science May 2016Medulloblastoma (MB) is the most common malignant pediatric brain tumor. Despite great improvements in the therapeutic regimen, relapse and leptomeningeal dissemination... (Review)
Review
Medulloblastoma (MB) is the most common malignant pediatric brain tumor. Despite great improvements in the therapeutic regimen, relapse and leptomeningeal dissemination still pose great challenges to the long-term survival of MB patients. Developing more effective strategies has become extremely urgent. In recent years, a number of malignancies, including MB, have been found to contain a subpopulation of cancer cells known as cancer stem cells (CSCs), or tumor initiating/propagating cells. The CSCs are thought to be largely responsible for tumor initiation, maintenance, dissemination, and relapse; therefore, their pivotal roles have revealed them to be promising targets in MB therapy. Our growing understanding of the major medulloblastoma molecular subgroups and the derivation of some of these groups from specific stem or progenitor cells adds additional layers to the CSC knowledge base. Herein we review the current knowledge of MB stem cells, highlight the molecular mechanisms relating to MB relapse and leptomeningeal dissemination, and incorporate these with the need to develop more effective and accurate therapies for MB patients.
Topics: Animals; Cell Separation; Drug Resistance, Neoplasm; Humans; Medulloblastoma; Meningeal Neoplasms; Neoplasm Recurrence, Local; Neoplastic Stem Cells; Signal Transduction
PubMed: 27171351
DOI: 10.1111/cas.12925 -
Journal of Neuro-oncology May 2023We and others have demonstrated that MYC-amplified medulloblastoma (MB) cells are susceptible to class I histone deacetylase inhibitor (HDACi) treatment. However, single...
PURPOSE
We and others have demonstrated that MYC-amplified medulloblastoma (MB) cells are susceptible to class I histone deacetylase inhibitor (HDACi) treatment. However, single drug treatment with HDACi has shown limited clinical efficacy. We hypothesized that addition of a second compound acting synergistically with HDACi may enhance efficacy.
METHODS
We used a gene expression dataset to identify PLK1 as a second target in MB cells and validated the relevance of PLK1 in MB. We measured cell metabolic activity, viability, and cycle progression in MB cells after treatment with PLK1-specific inhibitors (PLK1i). Chou-Talalay synergy calculations were used to determine the nature of class I HDACi entinostat and PLK1i interaction which was validated. Finally, the clinical potential of the combination was assessed in the in vivo experiment.
RESULTS
MYC-amplified tumor cells are highly sensitive towards treatment with ATP-competitive PLK1i as a monotherapy. Entinostat and PLK1i in combination act synergistically in MYC-driven MB cells, exerting cytotoxic effects at clinically relevant concentrations. The downstream effect is exerted via MYC-related pathways, pointing out the potential of MYC amplification as a clinically feasible predictive biomarker for patient selection. While entinostat significantly extended survival of mice implanted with orthotopic MYC-amplified MB PDX, there was no evidence of the improvement of survival when treating the animals with the combination.
CONCLUSION
The combination of entinostat and PLK1i showed synergistic interaction in vitro, but not in vivo. Therefore, further screening of blood-brain barrier penetrating PLK1i is warranted to determine the true potential of the combination as no on-target activity was observed after PLK1i volasertib treatment in vivo.
Topics: Mice; Animals; Histone Deacetylase Inhibitors; Medulloblastoma; Antineoplastic Agents; Cerebellar Neoplasms; Cell Line, Tumor
PubMed: 37183219
DOI: 10.1007/s11060-023-04319-1 -
Journal of Cancer Research and... Jan 2023Medulloblastoma (MB) is a heterogeneous disease, displaying distinct genetic profiles, with specific molecular subgroups. Various clinical, pathological and molecular...
BACKGROUND
Medulloblastoma (MB) is a heterogeneous disease, displaying distinct genetic profiles, with specific molecular subgroups. Various clinical, pathological and molecular variables have been associated with disease outcome and therefore utilised in risk stratification of patients.
OBJECTIVES
To perform molecular classification of medulloblastoma using surrogate immunohistochemistry (IHC) and associate molecular subgroups, histopathological types, and available clinicopathological parameters with overall survival (OS) of MB patients.
RESULTS
This study included 65 medulloblastoma patients. Immunohistochemical staining, using β-catenin YAP1 and GRB2-Associated Binding Protein 1 (GAB1) antibodies was used to classify MB cases into wingless signalling (WNT) activated, sonic hedgehog (SHH) activated, and non-WNT/non-SHH molecular subgroups. The relevant statistical analysis was done using GraphPad Prism version 9.3.0. Histological patterns included classic (40 cases, 62%), desmoplastic nodular (D/N) (14 cases, 22%), large cell/anaplastic (LC/A) (9 cases, 13%), medulloblastoma with extensive nodularity (MBEN) (1 case, 1.5%) and one special subtype, i.e., medulloblastoma with myogenic and melanotic differentiation. Molecular subgroups included WNT (4 cases, 6%), SHH (34 cases, 52%), and non-WNT/non-SHH (27 cases, 42%) subgroups. Histopathological types differed significantly according to tumor location, degree of anaplasia and molecular subgroups. Molecular subgroups differed significantly in age distribution and tumor location. The probability of survival was 78% and 68% after 1 and 2 years, respectively. Infants (<3 years of age), LC/A pattern, and TP53-mutant status among SHH subgroup conferred poor prognosis in our study. At the end of the study (at 65 months of maximum follow-up period) probability of survival was 51%.
CONCLUSIONS
Immunohistochemical analysis helps in molecular classification of medulloblastoma in majority of the cases as well as helps in predicting prognosis and treatment response.
Topics: Infant; Humans; Hedgehog Proteins; Medulloblastoma; Tertiary Care Centers; Prognosis; Cerebellar Neoplasms
PubMed: 38384024
DOI: 10.4103/jcrt.jcrt_1268_22