{"id":9,"date":"2020-04-23T17:05:26","date_gmt":"2020-04-23T17:05:26","guid":{"rendered":"https:\/\/lab.research.sickkids.ca\/taylor\/?page_id=9"},"modified":"2020-10-06T17:48:55","modified_gmt":"2020-10-06T17:48:55","slug":"research","status":"publish","type":"page","link":"https:\/\/lab.research.sickkids.ca\/taylor\/research\/","title":{"rendered":"Ependymoma"},"content":{"rendered":"

[vc_row][vc_column][vc_empty_space height=”50px”][\/vc_column][\/vc_row][vc_row][vc_column][vc_column_text]<\/p>\n

Ependymoma<\/span><\/b><\/h1>\n

Ependymoma is the third most common paediatric brain tumor and remains incurable in nearly 45 per cent of patients. Our recent integrated genomics research into the biology of ependymoma has demonstrated that mutation rates are very low and that epigenetic modifications are central to ependymoma pathogenesis. The current projects in our lab are driven by these findings and are aimed at <\/span><\/span>developing new therapies to improve the outcome for children with ependymoma.<\/span><\/span>\u00a0<\/span>[\/vc_column_text][\/vc_column][\/vc_row][vc_row][vc_column][vc_column_text]<\/p>\n

Ependymoma can be targeted by CAR T-cells<\/h3>\n

We have shown that<\/span> PFA-ependymomas express very high levels of a molecule named HER2 on their surface. My team, in collaboration with <\/span>the SU2C-USA Brain Immunotherapy Team, have<\/span> evidence<\/span>\u2014recently accepted in Nature Medicine\u2014<\/span>of strong anti-tumor activity on human PFA-ependymoma, using immunotherapy. Cancer immunotherapy is basically the treatment of a person’s cancer using certain parts of a person\u2019s own immune system to the fight disease. This can be done by either stimulating the patients own immune system to work harder to attack cancer cells. Or, in our case, by giving immune system components, such as man-made immune system cells. Immunotherapy has been used successfully to treat blood-borne cancers such as leukaemia and our experiments have shown that it can be adapted to work against solid tumours such as ependymoma.<\/span> Single agents used to treat cancer often show an initial response followed by resistance. We believe that treatment with epigenetic agents with additional immunotherapy treatment will increase the killing of the cancer cells.\u00a0<\/span>[\/vc_column_text][vc_empty_space][vc_single_image image=”702″ img_size=”large” add_caption=”yes” alignment=”center” style=”vc_box_shadow_3d” onclick=”link_image” css_animation=”fadeIn”][vc_empty_space][vc_column_text]In this work we therefore propose to develop and evaluate the combination of epigenetic therapy with immunotherapy for PFA-ependymoma in order to avoid resistance and increase effectiveness. These experiments should lead to the development of a multicentre clinical trial combining these two therapies for infants with PFA-ependymoma. As there are currently no other options to treat children with PFA-ependymoma, such a trial would accrue quickly. Any survival advantage in the trial would rapidly allow this treatment strategy to become the standard of care for children with this devastating disease.<\/span>\u00a0<\/span>[\/vc_column_text][\/vc_column][\/vc_row][vc_row][vc_column width=”1\/2″][vc_column_text]<\/p>\n

Ependymoma is driven by abnormal cellular metabolism<\/h3>\n

An almost complete lack of model systems has <\/span>previously <\/span>inhibited discovery of novel PFA therapies.\u00a0 <\/span>We recently discovered that b<\/span>oth <\/span>in vitro<\/span><\/i> and <\/span>in vivo<\/span><\/i>, the PFA hypoxic microenvironment controls the availability of specific metabolites to diminish methylation, and to increase both histone demethylation, and acetylation, all resulting in hypomethylation of H3K27.\u00a0 PFA ependymoma initiates from a cell lineage in the first trimester of human development where there is a known hypoxic microenvironment.\u00a0 Unique to PFA cells, even transient exposure to ambient oxygen (21%) results in i<\/span>rreversible cellular toxicity<\/span>. It<\/span> therefore <\/span>appears <\/span>that the unique metabolic environment of the developing human fetal hindbrain might contribute to the phenotype of PFA ependymoma through the influence of intermediary <\/span>metabolism on the epigenome, and that this mechanism might offer an opportunity for novel targeted therapy.<\/span>[\/vc_column_text][\/vc_column][vc_column width=”1\/2″][vc_empty_space][vc_single_image image=”553″ img_size=”medium” add_caption=”yes” alignment=”center” style=”vc_box_shadow_3d” onclick=”link_image” css_animation=”fadeIn”][\/vc_column][\/vc_row][vc_row][vc_column][vc_column_text]<\/p>\n

Current ependymoma research<\/h3>\n

While a number of stem cells and cancer cells have been shown to prefer growth in hypoxia, PFA ependymoma cells are unique in that they are permanently poisoned after only transient exposure to room air.\u00a0 <\/span>Our current and f<\/span>uture work <\/span>is focused on isolating<\/span> and study<\/span>ing<\/span> the cell of origin <\/span>so we can<\/span> determine if the unique metabolism of PFA cells is merely a reflection of their cell of origin in the early hindbrain, or an acquired phenotype.<\/span>\u00a0<\/span>[\/vc_column_text][\/vc_column][\/vc_row][vc_row][vc_column width=”1\/2″ offset=”vc_hidden-sm vc_hidden-xs”]