HD-MB03 is a novel Group 3 medulloblastoma model demonstrating sensitivity to histone deacetylase inhibitor treatment

Abstract

Medulloblastomas are the most common malignant brain tumors in childhood. Emerging evidence suggests that medulloblastoma comprises at least four distinct diseases (WNT, SHH, Group 3 and 4) with different biology, clinical presentation, and outcome, with especially poor prognosis in Group 3. The tight connection of biology and clinical behavior in patients emphasizes the need for subgroup-specific preclinical models in order to develop treatments tailored to each subgroup. Herein we report on the novel cell line HD-MB03, isolated from tumor material of a patient with metastasized Group 3 medulloblastoma, and preclinical testing of different histone deacetylase inhibitors (HDACis) in this model. HD-MB03 cells grow long term in vitro and form metastatic tumors in vivo upon orthotopic transplantation. HD-MB03 cells reflect the original Group 3 medulloblastoma at the histological and molecular level, showing large cell morphology, similar expression patterns for markers Ki67, p53, and glial fibrillary acidic protein (GFAP), a gene expression profile most closely matching Group 3 medulloblastomas, and persistence of typical molecular alterations, i.e., isochromosome 17q [i(17q)] and MYC amplification. Protein expression analysis of HDACs 2, 5, 8, and 9 as well as the predictive marker HR23B showed intermediate to strong expression, suggesting sensitivity to HDACis. Indeed, treatment with HDACis Helminthosporium carbonum (HC)-toxin, vorinostat, and panobinostat revealed high sensitivity to this novel drug class, as well as a radiation-sensitizing effect with significantly increased cell death upon concomitant treatment. In summary, our data indicate that HD-MB03 is a suitable preclinical model for Group 3 medulloblastoma, and HDACis could represent a therapeutic option for this subgroup.

HDAC and PI3K Antagonists Cooperate to Inhibit Growth of MYC- Driven Medulloblastoma

“…Our finding that HDACI are effective against mouse and human MYC- driven MB cells is consistent with previous studies showing that these drugs can impede growth of MB cell lines, and can induce cell death in genetically engineered models of SHH-driven MB (Milde et al, 2012; Shu et al, 2006; Spiller et al, 2006). Notably, LBH-589 was more potent than all the other HDACI we tested, including SAHA, one of the few HDACI that has been in clinical trials for MB (Fouladi et al, 2010; Witt et al, 2012).…”

Risk stratification of childhood medulloblastoma in the molecular era: the current consensus

“…Specific agents discussed included bromodomain inhibition, aurora kinase inhibition and histone deacetylases inhibitors. [1, 9, 18, 27, 38]…”

Molecular mechanisms and therapeutic targets in pediatric brain tumors

“…Among the best examples of drugs that can reprogram the epigenome are HDAC inhibitors, which have shown activity in a number of different cancers. Recent studies have revealed that G3-MB may be particularly sensitive to these drugs (87), particularly to s molecules that target class I HDACs (HDACs 1, 2, 3, and 8) (108,109). In addition to HDAC inhibitors, therapeutic agents targeting histone methylation have also been developed.…”