Summary
In previous research funded by the DTRF, Dr. Kris Vleminckx has developed a desmoid tumor model in the frog Xenopus tropicalis. Desmoid tumors can suppress the ability of the immune system to attack it and the current project will investigate if tazemetostat can reverse this suppressive ability in their frog model. Tazemetostat is currently approved for use in epithelial sarcomas, but the mechanism in desmoid tumors is unknown. Dr. Vleminckx has found that the drug affects the WNT/β-catenin pathway, but that mechanism does not kill or decrease the tumor cells. However, it is possible that this drug is affecting the immune system and allowing the immune system to attack the tumor. If successful, this research may lead to combinations of therapies or new therapies that involve activating the immune system to attack tumor cells.
Scientific Abstract
Using a genetic CRISPR/Cas9 based desmoid tumor model in the frog Xenopus tropicalis we have identified the gene EZH2, which encodes a member of the polycomb repressive complex 2 and is thereby involved in epigenetic regulation, as a dependency factor for desmoid tumors. Furthermore, a four-week treatment of Xenopus tropicalis carrying established desmoid tumors with the EZH2 inhibitor Tazemetostat caused a significant reduction in desmoid tumor volume. At the moment, the mode of action of Tazemetostat in this anti-tumor response is unknown. Interestingly, we found that Tazemetostat reduces Wnt pathway activity in human desmoid cell cultures but does not have an overt effect on cell proliferation or cell death in vitro. Therefore, given the well-established fact that solid tumors in which the Wnt/β-catenin pathway is activated are immunologically cold and thereby insensitive to immune checkpoint inhibition, we postulate that the regression in desmoid tumor volume observed in the Xenopus model upon Tazemetostat treatment counters this immunosuppressive environment and allows the engagement of a natural anti-tumor immune response. We hypothesize that the reduced Wnt signaling activity induced by Tazemetostat alleviates the immune checkpoint controls and allows the occurrence of a T-cell mediated immune response towards the desmoid tumor. Using a range of genetic experiments in Xenopus tropicalis this hypothesis will be investigated.
