In several of these cases, activation of HH-GLI signaling is mediated by overproduction of HH ligands (e.g., prostate cancer), loss-of-function mutations in <i>PTCH1</i> or gain-of-function mutations in <i>SMO</i>, which occur in the majority of basal cell carcinoma (BCC), SHH-subtype medulloblastoma and rhabdomyosarcoma.
Medulloblastoma (MB) is a pediatric malignant brain tumor composed of four different subgroups (WNT, SHH, Group 3, Group 4), each of which are a unique biological entity with distinct clinico-pathological, molecular, and prognostic characteristics.
Recent molecular analyses of pediatric and adult MB have classified these tumors into at least four individual molecular subgroups (SHH, WNT, group 3, and group 4) with distinct demographics, histology, and prognosis.
Inhibition of LDHA significantly reduced growth of both mouse and human <i>MYC</i>-driven tumors but had little effect on normal cerebellar cells or SHH-associated medulloblastoma.
However, there were no reports investigating the relationships between preoperative hematological markers and the prognosis of medulloblastoma (MB) patients based on the molecular subgroups (WNT, SHH, Group 3, and Group 4).
About 30% of patients experience relapse after treatment, possibly because of our inability to identify and eliminate the cancer stem cells.Zhang et al. recently investigated these cells in the SHH subgroup of medulloblastoma and identified drugs that may target them.
Herein we report two adolescent patients with Group 4 and SHHmedulloblastoma, where vinblastine successfully replaced vincristine with resolution of their peripheral neuropathy.
MB tumors belonging to SHH molecular subgroup, with TP53<sup>MUT</sup>, would be the ones that present high risk in relation to VA use during the treatment, while TP53<sup>WT</sup> MBs can benefit from VA therapy, both SHH and groups 3 and 4.
We have implemented several biochemical experiments using human MB tumor microarray (TMA) and pediatric MB cell lines, derived from high-risk SHH-TP53-mutated and MYC-amplified Non-WNT/SHH tumors.
Biomarkers were identified applying stringent selection filters and Linear Discriminant Analysis (LDA) method, and validated using DNA methylation microarray data, bisulfite pyrosequencing, and direct-bisulfite sequencing.<b>Results:</b> Using a LDA-based approach, we developed and validated a prediction method (<sup>Epi</sup>WNT-SHH classifier) based on six epigenetic biomarkers that allowed for rapid classification of medulloblastoma into the clinically relevant subgroups WNT, SHH, and non-WNT/non-SHH with excellent concordance (>99%) with current gold-standard methods, DNA methylation microarray, and gene signature profiling analysis.
The parallel increase of c-Met and MAP4K4 expression in SHHMB could predict an increased potential of these tumors to infiltrate brain tissue and cause metastatic disease.
Medulloblastoma (MB) is an embryonal tumour that originates from genetic deregulation of cerebellar developmental pathways and is classified into 4 molecular subgroups: SHH, WNT, group 3, and group 4.
Our study demonstrates the clinical utility of CD271 as both a diagnostic and prognostic tool for SHHmedulloblastoma tumors and reveals a novel role for MEK inhibitors in targeting CD271<sup>+</sup> SHHmedulloblastoma cells.<b>Significance:</b> This study identifies CD271 as a specific and novel biomarker of SHH-type medulloblastoma and that targeting CD271<sup>+</sup> cells through MEK inhibition represents a novel therapeutic strategy for the treatment of SHHmedulloblastoma.<i></i>.
Targeting of oncogene-driven replicative stress as therapeutic option for high-risk medullobastoma was assessed using a panel of medulloblastoma cells differing in their c-Myc expression [i.e. group SHH (c-Myc low) vs. group 3 (c-Myc high)].
Indeed, our results delineate anti-neoplastic activity of Axitinib in medulloblastoma cell lines modelling the most aggressive c-myc-amplified Non-WNT/Non-SHH and SHH-TP53-mutated tumours.
Prognostic biomarkers and models identified were validated in an independent, demographically matched cohort (n=70) of medulloblastoma patients with non-WNT/non-SHH standard-risk disease treated with conventional therapies (maximal surgical resection followed by adjuvant craniospinal irradiation [all patients] and chemotherapy [65 of 70 patients], at UK Children's Cancer and Leukaemia Group and European Society for Paediatric Oncology (SIOPE) associated treatment centres between 1990 and 2014.
A Kaplan-Meier survival curve and multivariate Cox regression demonstrated that high M1 expressers showed worse overall survival (OS) and progression-free survival (PFS) than low M1 expressers in SHHMB, with relative risk (RR) values of 11.918 and 6.022, respectively.