Molecular stratifications, biomarker candidates and new therapeutic options in current medulloblastoma treatment approaches

Abstract

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, WNTactivated, 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-specific markers of prognosis can enable a more layered risk stratification with additional subtypes within each primary subgroup. Here, we summarize subgroup-specific genetic alterations and their utility in current treatment strategies. The transition toward molecularly targeted interventions for newly diagnosed MBs remains slow, and prospective trials are needed to confirm stratifications based on molecular alterations. At the same time, numerous studies focus at fine-tuning the intensity of invasive radio-and chemotherapies to reduce intervention-related long-term morbidity. There are an increasing number of immunotherapy-based treatment strategies including immune checkpoint-inhibitors, oncolytic viruses, CART therapy, and NK cells in recurrent and refractory MBs. Although most trials are in early phase, there is hope for therapeutic breakthroughs for advanced MBs within the next decade.

Neurotrophin Signaling in Medulloblastoma

“…For example, among brain tumors, glioblastoma, pilocytic astrocytoma, and pontine glioma can show gene fusions involving NTRK2 or NTRK3 [63,87,142,143]. A number of small-molecule acting as pan-Trk inhibitors are currently being evaluated in clinical trials [144][145][146]. A recent phase 1 and 2 clinical study examining the effects of the pan-Trk inhibitor larotrectinib in children and adults with various types of peripheral solid cancers harboring NTRK gene fusions found pronounced and durable responses regardless of patient age or tumor type [147].…”

Advanced MRI Findings in Medulloblastomas: Relationship to Genetic Subtypes, Histopathology, and Immunohistochemistry

“…A neuroradiologist ( J.R.) with 4 years of experience in diagnostic neuroradiology who was blinded to neuropathological and clinical data performed ADC measurements in each presurgical MRI, using a dedicated picture archiving and communication system (syngo Imaging, Siemens Healthineers). In detail, ROIs with a size of 30-100 mm 2 were manually placed within the solid tumor components as previously described, 22,27 carefully avoiding inhomogeneous regions such as cysts or hemorrhage. To decrease the amount of discordant values, measurements were carried out thrice for each slice in each patient, yielding at least six to nine ROIs.…”

“…Conventional prognostic factors include patient age, tumor volume, extent of surgical tumor removal, any metastasis of tumor cells along the cerebrospinal fluid pathways, and the histopathological subtype. 2 Since the WHO classification of Central Nervous Tumors has been updated in 2016, diagnosis of medulloblastoma now demands for genetic typing additionally to histopathology, 3,4 enabling a significantly improved prognostic evaluation. The worst prognosis is seen in sonic hedgehog (SHH)-activated tumors, partic-…”

Review of PP2A Tumor Biology and Anti-Tumor Effects of PP2A Inhibitor LB100 in the Nervous System

“…Medulloblastoma (MB) is the most common primary malignant brain tumor in the pediatric population, accounting for nearly 20% of all CNS tumors in children [97,98]. The standard treatment regimen for these tumors involves maximal gross total resection followed by radiotherapy and chemotherapy [99].…”