Stopping cancer tumours in their tracks

BC researchers develop new non-toxic cancer treatment. Slowing tumour growth by cutting off blood supply

By Mary-Ev Anderson

"Identification of a novel therapeutic target is exciting," says Dr Shoukat Dedhar. He should know. Along with MD/PhD student Clara Tan and a team of researchers, he's recently made a significant step forward in the fight against cancer. They've demonstrated that it's possible to inhibit tumour angiogenesis, the growth of new blood vessels, and thus inhibit tumour growth by blocking the enzyme integrin-linked kinase (ILK).

The research was carried out at the British Columbia Cancer Agency and published in the January issue of Cancer Cell. "There's a lot of potential which is realizable," says Dr Dedhar, senior scientist and UBC professor of biochemistry and molecular biology. "We have the inhibitors that hit the target. Now they have to be developed for clinical use."

The aim of the study was to find out whether ILK promotes angiogenesis, the formation and differentiation of blood vessels, in tumours. Integrins are cell surface proteins which bind to components of the extracellular matrix. A kinase catalyzes the transfer of a phosphate group. Dr Dedhar and his colleague Dr Greg Hannigan, of Sunnybrook Health Sciences in Toronto, discovered ILK in 1996.

THE PROSTATE CANCER TEST
Dr Dedhar's team was able to prevent angiogenesis in human tumours transplanted in mice, and significantly slow down the growth of the tumours by inhibiting the function of ILK. Immunodeficient mice were injected with human prostate cancer cells in the left and right flank regions. One week after treatment with an ILK inhibitor, when tumours were established, one tumour was removed from each mouse and treatment resumed for three more weeks. The mice showed statistically significant suppression of blood vessel infiltration into the tumour after one week of treatment, and suppression of tumour growth after three weeks of treatment, with no obvious side effects or weight loss.

The team concluded that ILK has great therapeutic promise for tumour angiogenesis. They found that ILK is essential to two key aspects of tumour angiogenesis because it controls both the production and action of a protein called vascular endothelial growth factor (VEGF). Tumour cells secrete VEGF which in turn stimulates the formation and growth of new blood vessels into the tumour from adjacent blood vessels. The study showed that inhibiting ILK blocks both these functions.

"To get blood, the tumour produces VEGF, which diffuses out from the tumour," says Ms Tan. When it comes into contact with a neighbouring blood vessel, VEGF prompts endothelial cells to migrate and form capillaries. "Endothelial cells organize themselves into tubes," she says, "building bridges from existing blood vessels to the tumour."

Inhibiting ILK activity decreases VEGF production by decreasing the levels of HIF-1_ protein. By blocking ILK, the compound inhibits both tumour production and the nearby endothelial cells' growth response.

POTENTIAL BROAD APPLICATION
"[This study is] very scientifically important," says Dr Judah Folkman, the Harvard professor of pediatric surgery and cell biology who pioneered angiogenesis research. "Angiogenesis inhibitors in general have a much broader spectrum than chemotherapy because they're not dependent on a single type of cancer cell, but on the main fuel line." He thinks ILK inhibition could apply to most solid tumour cancers. "About 60-80% of human tumours start by making VEGF," he says. "Some tumours have different ways of stimulating capillary blood vessels and you'd have to stop them in a specific way."

According to Dr Folkman, the compound is "very novel" because it targets two pathways in the angiogenic process: "Most angiogenesis inhibitors block one or the other," he says. One, Iressa, which is available in Canada, blocks VEGF production, he says. Endothelial cells' response to VEGF and to many other angiogenic factors is frozen by Endostatin, now in phase II clinical trials. Another drug, Avastin, neutralizes VEGF after it has been secreted by a tumour, before it acts on nearby endothelial cells. It was "a resounding success" in recent phase III clinical trials for colorectal cancer.

"The combination of Avastin and our inhibitors may work really well," Dr Dedhar says, "because you're completely shutting down the formation of VEGF, plus its downstream action." Chemotherapy or radiation could then destroy the remaining tumour.

The compound is expected to go to phase I clinical trials on human breast and prostate cancers at the BC Cancer Agency early next year. Dr Dedhar's research team is currently investigating whether ILK also controls lymphatic vessel growth.