Donnelly Researchers Gary Bader and Amy Caudy Take on Brain Cancer
Donnelly Centre researchers Drs. Gary Bader and Amy Caudy to fight childhood and adult brain cancers as part of an interdisciplinary research team, it was announced this month. The Cancer Stem Cell Dream Team is led by Drs. Peter Dirks, from the Hospital for Sick Children (SickKids) in Toronto, and Samuel Weiss, of the University of Calgary.
Backed by the Stand Up to Cancer Canada (SU2C) initiative, the team will gather detailed biological profiles on brain cancer stem cells (BCSCs) that drive cancer occurrence. The researchers will catalogue any changes in the cells’ genetic code, as well as in epigenetic programming that controls gene activity.
At the Donnelly Centre, Caudy’s team will further analyze how these cells metabolize nutrients, while Bader’s team of computational biologists will make sense of the vast amount of data that will be generated by the consortium. Critically, these new insights are expected to lead to tangible advances in drug development in the hope of extending the lives of patients who currently have few options.
"I think we’ll learn many basic things about cancer, and I hope that we may be able to find better drug targets. Right now for we have so little to offer these children with glioblastoma."
Despite advances in cancer care, brain tumours remain the most difficult to treat. The average survival for glioblastoma, the most common form, is entrenched at just 15 months following diagnosis. To gain a deeper understanding of the disease, the researchers will examine cancer stem cells from 70 patients. Most of these tumours are of the glioblastoma type, with a smaller portion of ependymoma, the third most common childhood cancer, with a similarly poor outcome.
“We want to collect an unprecedented amount of information on patient tumour stem cells and integrate all the data together. The goal is to come up with a list of molecular networks that are acting in these cells that could be attacked by drugs,” says Bader, who is also a professor in U of T’s Department of Molecular Genetics and an associate member of the Lunenfeld-Tanenbaum Research Institute at Mount Sinai Hospital in Toronto.
This approach was previously successful when Bader and colleagues from SickKids integrated different types of data for ependymoma and identified a weakness - a drug target - in a patient’s tumour. Having found the right drug that only killed the tumour cells, the doctors were able to successfully treat two patients. A part of the Dream Team’s funding will be to kick start a clinical trial for this drug in the hope of it becoming the first treatment for ependymoma.
Cancer stem cells are like the stem cells’ evil twins. Normally, the stem cells help our bodies grow and repair, due to their ability to turn into any cell type. But they can also go haywire to become cancer stem cells, locked in an eternal state of proliferation. Instead of making useful cell types, such as brain or blood cells, cancer stem cells fuel tumour growth.
Changes in cell state are driven by sweeping shifts in epigenetic marks – these are chemical tags that reside near the genes and act as on/off switches. Scientists think that cancer stem cells arise from errors in epigenetic marks that ramp up those genes that favour cell division. A big part of the team's effort will be to decipher the epigenetic programming in tumour stem cells.
In particular, Caudy’s team will home in on a metabolite called 2-hydroxyglutarate (2HG) that can reset epigenetic marks to push cells into a state where they divide more. While high levels of 2HG have been linked to glioblastoma, as well as to other types of cancer, it seems that cells have several different ways to stockpile the chemical. Thanks to new technology developed in collaboration with Dr. Adam Rosebrock, Caudy will be able to measure precise amounts of 2HG in the BCSCs in search of its sources.
“I think we’ll learn many basic things about cancer, and I hope that we may be able to find better drug targets. Right now for we have so little to offer these children with glioblastoma,” says Caudy, also a professor in the Department of Molecular Genetics.
The drug discovery arm of the project is fast-tracked through the Structural Genomics Consortium (SGC), a Toronto-based public-private partnership that facilitates collaboration between the pharmaceutical industry and academic research labs.
The team’s research is supported by $11.7 million, funded by Stand Up To Cancer Canada, Genome Canada, the Canadian Institutes of Health Research, the Cancer Stem Cell Consortium and the Ontario Institute for Cancer Research (OICR). OICR will also provide up to $1.2 million for clinical trials in Ontario.