Targeting Cancer at its Roots

Glioblastoma is the most aggressive cancerous brain tumour in adults and remains one of the most difficult of the cancers to treat.  Offered radiation therapy and chemotherapy, 1,500 Canadian adults every year begin treatment knowing that with an average survival of 15 months, glioblastoma will soon take over their brain, with fatal consequences. Glioblastoma also affects about 150 children in Canada every year.

New research led by University of Toronto’s Faculty of Medicine and The Hospital for Sick Children (SickKids) has found clues to how glioblastoma and possibly other cancers proliferate. Scientists have found that the 3D structure of DNA, or the way that DNA is folded in a cancer cell, can determine its ability to generate more cancer cells and maintain tumour growth. The study is published in the November 25 online edition of Cancer Cell.

The researchers identified a new function for a protein called histone 3.3 (H3.3). This protein is needed to fold or shape the DNA in its normal structure. In adult glioblastoma cells this protein occurs in lower than normal levels. Lower levels of this protein give rise to an irregular DNA shape, which prevents the cells from maturing. The cells are locked in a stem cell state, producing a small pool of cells in the glioblastoma called cancer stem cells.

“Although these cells are not numerous in a tumour, they are nonetheless fundamental to its growth, as they provide an everlasting supply of progeny that constitute the bulk of the tumour and drive tumour growth,” says Marco Gallo, first author of the study and post-doctoral fellow in Professor Peter Dirks’ lab.

Researchers were also able to determine how levels of H3.3 are suppressed. They identified a protein in glioblastoma stem cells that turns off the gene responsible for producing the DNA folding protein.

According to Dirks, co-principal investigator of the study and Professor of Neurosurgery, Molecular Genetics and Laboratory Medicine and Pathobiology, this is the first study to make a link between the overall architecture of DNA and the tumour-propagating properties of cancer cells.  In this investigation, the scientists were able to change the shape of the DNA by controlling the levels of the folding protein and by exposing the tumour cells to two drugs known to affect DNA structure. By changing the shape in this manner, the scientists were able to reduce the tumour cells’ ability to divide and grow.

“Our findings offer proof-of-principle that new drugs that alter DNA structure hold promise to suppress cancer stem cells’ ability to replenish the tumour, offering new weapons to attack cancer cells at its roots,” says Dirks, who is also Staff Neurosurgeon and Senior Scientist at SickKids and Principal Investigator at The Arthur and Sonia Labatt Brain Tumour Research Centre at SickKids and at the University of Toronto.

Mathieu Lupien, a Professor in the Department of Medical Biophysics and scientist at the Princess Margaret Cancer Centre – University Health Network, is the co-principal investigator of the study.