Group 3 medulloblastoma

Group 3 medulloblastomas are characterized by frequent amplifications of the oncogene MYC, a high incidence of metastasis, and poor prognosis despite aggressive therapy.

Group 3 molecular subgroup patients have the highest relapse rates and after standard-of-care have a 20% survival. Group 3 tumors have high expression of GABRA5, which codes for the α5 subunit of the γ-aminobutyric acid type A receptor (GABAAR).

Kallay et al., performed analysis of GABR and MYC expression in MB tumors and used molecular, cell biological, and whole-cell electrophysiology approaches to establish presence of a functional 'druggable' GABAAR in group 3 cells.

Analysis of expression of 763 MB tumors reveals that group 3 tumors share high subgroup-specific and correlative expression of GABR genes, which code for GABAAR subunits α5, β3 and γ2 and 3. There are ~ 1000 functional α5-GABAARs per group 3 patient-derived cell that mediate a basal chloride-anion efflux of 2 × 109 ions/s. Benzodiazepines, designed to prefer α5-GABAAR, impair group 3 cell viability by enhancing chloride-anion efflux with subtle changes in their structure having significant impact on potency. A potent, non-toxic benzodiazepine ('KRM-II-08') binds to the α5-GABAAR (0.8 µM EC50) enhancing a chloride-anion efflux that induces mitochondrial membrane depolarization and in response, TP53 upregulation and p53, constitutively phosphorylated at S392, cytoplasmic localization. This correlates with pro-apoptotic Bcl-2-associated death promoter protein localization.

GABRA5 expression can serve as a diagnostic biomarker for group 3 tumors, while α5-GABAAR is a therapeutic target for benzodiazepine binding, enhancing an ion imbalance that induces apoptosis 1).

Faria et al. investigated several potential small molecule inhibitors to target Group 3 medulloblastomas based on gene expression data using an in silico drug screen. The Connectivity Map (C-MAP) analysis identified piperlongumine as the top candidate drug for non-WNT medulloblastomas and the cyclin-dependent kinase (CDK) inhibitor alsterpaullone as the compound predicted to have specific antitumor activity against Group 3 medulloblastomas. To validate the findings they used these inhibitors against established Group 3 medulloblastoma cell lines. The C-MAP predicted drugs reduced cell proliferation in vitro and increased survival in Group 3 medulloblastoma xenografts. Alsterpaullone had the highest efficacy in Group 3 medulloblastoma cells. Genomic profiling of Group 3 medulloblastoma cells treated with alsterpaullone confirmed inhibition of cell cycle-related genes, and down-regulation of MYC.

This results demonstrate the preclinical efficacy of using a targeted therapy approach for Group 3 medulloblastomas. Specifically, they provide rationale for advancing alsterpaullone as a targeted therapy in Group 3 medulloblastoma 2).

Kallay L, Keskin H, Ross A, Rupji M, Moody OA, Wang X, Li G, Ahmed T, Rashid F, Stephen MR, Cottrill KA, Nuckols TA, Xu M, Martinson DE, Tranghese F, Pei Y, Cook JM, Kowalski J, Taylor MD, Jenkins A, Pomeranz Krummel DA, Sengupta S. Modulating native GABA(A) receptors in medulloblastoma with positive allosteric benzodiazepine-derivatives induces cell death. J Neurooncol. 2019 Feb 6. doi: 10.1007/s11060-019-03115-0. [Epub ahead of print] PubMed PMID: 30725256.
Faria CC, Agnihotri S, Mack SC, Golbourn BJ, Diaz RJ, Olsen S, Bryant M, Bebenek M, Wang X, Bertrand KC, Kushida M, Head R, Clark I, Dirks P, Smith CA, Taylor MD, Rutka JT. Identification of alsterpaullone as a novel small molecule inhibitor to target group 3 medulloblastoma. Oncotarget. 2015 May 28. [Epub ahead of print] PubMed PMID: 26061748.
  • group_3_medulloblastoma.txt
  • Last modified: 2019/02/08 13:09
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