Targeting Cancer at Its Roots

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Protein in cancer stem cells could represent a new target to treat aggressive brain cancer.
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Cancer stem cells, which enable some tumours to return after treatment, are like the bulbs of perennial plants. As long as the bulb is present, the plant will grow back.
A UHN study has revealed a new therapeutic approach that could help to treat glioblastoma, the most common and most aggressive form of brain cancer in adults. In 2017, glioblastoma claimed the life of Gord Downie, the former frontman of Canada’s iconic rock band, The Tragically Hip.
Glioblastoma is a deadly cancer diagnosed in approximately a thousand Canadians every year. Less than 5% of these individuals survive more than five years. The rates of survival are dismal because most of these brain tumours do not respond to current treatments. New and more effective treatments are therefore urgently needed for this disease.
In the study, Dr. Valerie Wallace, a Senior Scientist at the Krembil Research Institute (UHN), and her trainee Dr. Ahmed El-Sehemy discovered that the protein Norrin plays an important role—albeit a complicated one—in the growth and proliferation of glioblastoma tumours.
“Norrin has been implicated in blood vessel formation in the brain, eye and inner ear, and the regulation of brain cell behaviour. Our findings indicate that Norrin is present in a wide range of brain tumours and that higher levels of the protein are linked to better patient survival,” says Dr. Wallace.
Glioblastoma tumours contain a small number of specialized cells known as cancer stem cells, which can give rise to new tumour cells. These stem cells are widely believed to be responsible for the cancer’s resistance to treatment and its recurrence. Accordingly, targeting these cells could be the key to treating glioblastoma.
The researchers found that Norrin affects the growth and proliferation of a tumour’s cancer stem cells. In stem cells with high levels of the ASCL1 protein, Norrin promoted cell growth, whereas in cells with low ASCL1 levels, Norrin inhibited growth. Although ASCL1’s role in brain cancer is not entirely clear yet, the protein is known to be involved in the generation of brain cells during development.
Dr. Wallace comments, “Our study reveals an unanticipated role of Norrin in brain cancer progression. Norrin could be a potential therapeutic target for glioblastoma tumours and may inform the design of patient-specific treatments.”
This work was supported by the Cancer Research Society, the Canadian Institutes of Health Research and the Toronto General & Western Hospital Foundation. VA Wallace holds a Tier 1 Canada Research Chair in Retina Regeneration.
El-Sehemy A, Selvadurai HJ, Ortin-Martinez A, Pokrajac NT, Mamatjan Y, Tachibana N, Rowland KJ, Lee L, Park NI, Aldape KD, Dirks P, Wallace VA. Norrin mediates tumor-promoting and -suppressive effects in glioblastoma via Notch and WNT. J Clin Invest. 2020 Mar 17. doi: 10.1172/JCI128994.

Dr. Valerie Wallace, Senior Scientist, Krembil Research Institute. Photo courtesy of the Globe and Mail.