Glioblastoma is the most common type of brain tumor in adults, against which there is no effective treatment. Recently a new drug - an EZH2 inhibitor- raised the attention of cancer researchers. This drug silences the protein EZH2, which is present in high concentrations in glioblastoma cells and various other tumor types. Research has shown that EZH2 blocks the production of other proteins that have anti-cancer properties. So, theoretically, by silencing EZH2, blocked anti-cancer proteins can be reactivated to repress tumor growth. Currently, an EZH2 inhibitor is being tested for safety and efficacy in a clinical trial with lymphoma patients.
However, silencing EZH2 can be dangerous, as research from the group of Maarten van Lohuizen now shows. Using glioblastoma mouse models and cultured human glioblastomas, postdoctoral researcher Nienke de Vries discovered that EZH2 inhibition initially is very effective against this type of cancer. However, upon prolonged and continuous treatment the tumors become resistant. Moreover, the changes in the tumor that cause resistance also result in cancer cells that proliferate even more rapidly than before, making the tumors more aggressive.
"We observed that the cancer cells change their identity and resemble an aggressive type of undifferentiated stem cells", says Van Lohuizen. "Furthermore, we discovered that these changes don't occur because of new mutations; they are epigenetic." Epigenetic here means that the activity and regulation of many genes in the tumor cells is altered due to prolonged EZH2 inhibition. This results in enhanced growth rate and increased DNA repair activity in the tumor cells, rendering them insensitive against chemotherapy with temozolomide.
This doesn't mean the new drug has to be discarded. Van Lohuizen: "Our research also shows that short-term EZH2 inhibition is effective without these unwanted effects. The epigenetic changes within the tumor cells don't occur immediately, it takes some time for them to develop." So the solution could be to design a drug regime in which the use of the inhibitors is meticulously timed, administering them long enough to be effective but suspending the therapy before resistance can evolve. Van Lohuizen: "Another possible solution could be to design a combination therapy, in which EZH2 inhibitors are given in combination with another drug that counters the harmful effects." He also emphasizes: "One should keep in mind that this a type of cancer for which at the moment there is no effective therapy. So anything that might possibly work, offers hope and deserves exploration."