A novel combination therapy that could prevent resistance to cytostatics, which are commonly used in the treatment of medulloblastoma, has been discovered by researchers at the Karolinska Institutet in Sweden. The findings of this preclinical study were published in Nature Communications and could lead to improved outcomes for children with this severe type of malignant brain tumor.
In particular, the therapy could prove most promising for children whose brains are still developing, as these children have the highest risk of radiotherapy-induced injury.
During the development of therapeutic resistance, cancer cells produce an enzyme that is able to repair DNA damage induced by chemotherapy. This can occur during treatment with temozolomide in medulloblastoma.
In the present study, conducted in mice and human tumor cells, the researchers discovered a method of inhibiting MGMT, a key component of cytostatic resistance.
They also reported that beta-catenin, a signaling molecule in the ‘Wingless’ pathway, can regulate MGMT production in cancerous cells. Thus, by blocking Wingless/beta-catenin, the MGMT enzyme is inhibited and this in turn prevents cytostatic resistance.
The team used a combination of temozolomide and Wingless inhibitors in mice and on human tumor cells to render cells susceptible to the anticancer effect of temozolomide.
Malin Wickström, one of the researchers from Karolinska Institutet, commented on future research: “Now that we’ve tested already available drugs, the published results enable us to move on to clinical trials relatively quickly, which is very good news indeed.”
Sources: Wickström M, Dyberg C, Milosevic J et al. Wnt/β-catenin pathway regulates MGMT gene expression in cancer and inhibition of Wnt signalling prevents chemoresistance. Nature Communications. doi: 10.1038/ncomms9904 (2015); Karolinska Institutet press release