Experimental combination therapy of brain cancer cell models

Abstract: Epigenetic alterations and aberrant expression of genes controlling epigenetic mechanisms have been identified in several cancers, including medulloblastoma and glioma, the most common primary brain tumors in children and adults, respectively. We have been investigating if combination therapy using histone deacetylase inhibitors (HDACi) and receptor tyrosine kinase inhibitors (RTKi) will enhance glioblastoma and medulloblastoma cell killing. In medulloblastoma studies we combined a DNA methylation inhibitor, an HDAC inhibitor together with tyrosine kinase inhibitors. In the first study (Paper I) we have shown that combining HDACi with the RTKi gefitinib and vandetanib resulted in enhanced cell killing and reduced clonogenic survival. Mono-therapy using HDACi sodium 4-PB induced minor cell killing effects in neither of the analyzed cell lines. Similar results were observed after mono-therapy using gefitinib or vandetanib. However the combination of 4-PB with gefitinib resulted in significantly increased cell death compared to mono treatment in both cell lines. Furthermore, the double therapy resulted in a significant decrease in colony formation. The second study (Manuscript) showed that combination of drugs that inhibit two of the most important epigenetic factors (gene methylation and post-translational modifications of protein histone-associated DNA with small molecule inhibitors of receptor tyrosine kinase) enhances cell killing in two medulloblastoma cell lines. The HDACi, 4-phenylbutyrate (4-PB) and the demethylation agent, 5-Aza-2’deoxycytidine (5-Aza-dC) had minor effects on medulloblastoma cell cytotoxity when used as single agents. A significant enhancement in cell cytotoxity was seen when these drugs were combined with imatinib or sorafenib. Triple combinations resulted in accumulation of cells with subG1 DNA content and were associated with a decrease in the expression of histone deacetylase genes and reduced global methylation. This occurred together with an increase in apoptosis. Taken together these results suggest that combinations of these drugs may be beneficial in the treatment of medulloblastoma.