Vancouver - BC Cancer Agency researchers have found a connection between a key tumour supressor gene and a protein that plays a major role in the growth and spread of cancer. The discovery could set the stage for a promising new approach to cancer treatment.

The research findings of BCCA senior scientist Dr. Shoukat Dedhar are being published on-line today in the Proceedings of National Academy of Sciences (www.pnas.org, in Washington, DC. The PNAS selected Dr. Dedhar's work based on the groundbreaking advances he and his team have made into the role of the cancer-causing gene, Integrin-linked Kinase (ILK).

The paper reveals that ILK protein is hyperactive in prostate cancer cells that have lost the key tumour supressor PTEN. In normal cells PTEN keeps ILK in check, but in the absence of a functional PTEN, ILK stops tumour cells from dying-a process necessary to preventing cancer progression. Researchers have also determined that PTEN and ILK are components of a "Master Switch" in the cellular signalling pathways that control cell survival, growth and movement.

Under normal circumstances, cells grow, divide and die in an organized fashion. When that process goes awry however, and cells don't die, (for example, due to the dysregulation of ILK), they will continue to grow and divide at an uncontrollable rate, forming cell masses (tumours). These masses then spread to other parts of the body (metastasis).

It's now known that the gene for PTEN is mutated or deleted in 60% of all solid cancers and research carried out in Dedhar's laboratory indicates that ILK is hyperactive in many of these cancers - including cancers of the prostate, breast, brain, lung and colon.

Dr. Dedhar believes that by inhibiting ILK through chemical compounds, researchers may be able to prevent tumours from growing and spreading.

"The discovery of ILK, and the role it plays in causing cancer, may set the stage for promising new approaches to cancer therapy," says Dr. Dedhar. "We now know that if we inhibit ILK, we might be able to treat tumours in novel ways. This is an exciting step for cancer research in British Columbia."

Dr. Dedhar's team is now collaborating with Kinetek Pharmaceuticals (www.kinetekpharm.com of Vancouver on developing compounds that will inhibit the activity of ILK. The chemical compounds (inhibitors) developed to date have shown some excellent preliminary results.

During pre-clinical trials, the ILK inhibitors induced cell death of prostate cancer cells and reduced the growth of tumours in mice. In effect, the inhibitors produced a highly targeted, triple-hit attack on tumours by inducing cell death, blocking the formation of new blood vessels (Angiogenesis) - a process critical to a tumour's survival -- and preventing cells from migrating to other areas.

"This is both amazing and exhilarating," said Dr. Dedhar. "Inhibiting ILK many not only result in the inhibition of growth of the primary tumour, but may also lead to the inhibition of the subsequent spread of the tumour cells."

"And unlike standard chemotherapy agents," he adds, "these inhibitors do not appear to kill or harm healthy cells, thus producing few side effects."

"This is exciting news for cancer research in B.C. and for cancer patients everywhere," said Dr. Victor Ling, vice-president of research at the BCCA."A targeted therapy with fewer side effects will mean better results for those living with cancer."

The National Cancer Institute of Canada and the Terry Fox Foundation funds Dr. Dedhar's project. It's part of a program grant to study prostate cancer progression. Dr. Dedhar has been studying ILK and its connection to the tumour supressor gene PTEN since he and his colleague, Dr. Greg Hannigan of Sunnybrook Health Sciences in Toronto, first discovered ILK in 1996. Dr. Dedhar is part of the BC Cancer Agency's prostate program which together with Vancouver Hospital and Health Sciences Centre for the Centre of Excellence for Prostate Cancer Research.

Phase One clinical trials on ILK inhibitors are expected to begin within 24 months.

About clinical trials

The research discussed in this news release is still very much in the early stages. It will be two years before the first of a series of trials in humans begins. Clinical trials take place in several phases, usually three.

Phase I trials -  first step in testing new treatments in humans. At this stage, researchers look for the best way to give the treatment, and determine its safety and side-effects. These studies usually include a small number of patients who can not be helped through other means.

Phase II trials - focuses on learning whether the new therapy has an anti-cancer effect on specific cancers. These trials, too, are only open to a small number of people because of the risks and unknowns.

Phase III trials - compares the results of patients taking the new treatment with those of people taking standard treatments. These trials may include hundreds of patients.

To take a new treatment through all three phases, which usually occur one after the other, can take up to ten years.

Kinetek Pharmaceuticals is a biopharmaceutical company specializing in therapeutics based on the modulation of disease-related sign transduction pathways. The company has focused its research and development programs on the discovery and development of small molecule drugs aimed at blocking the action of cell signaling enzymes to treat cancer, diabetes and other chronic diseases.

Background Notes for "master switch" gene

What are ILK and PTEN?

Integrin-linked kinase (or ILK) is perhaps the most important enzyme in the integrin and growth factor signaling pathways. ILK functions as a true "master switch" because it receives a wide range of extracellular messages, which it responds to by sending out signals that control cellular functions associated with tumor growth and migration.

BC Cancer Agency molecular biologist Dr. Shoukat Dedhar and post-doctoral fellow Greg Hannigan discovered ILK in 1996 when they were studying the integrin signaling pathway. "We found that ILK activity is very low in healthy cells", explains Dr. Dedhar. "In cancer cells, however, ILK activity increases as a result of malfunctions in upstream components of the integrin and growth factor signaling pathways. Our research showed that overactive ILK can transform normal cells into abnormal cells - which can ultimately lead to tumor formation."

Dr. Dedhar's research has recently determined that ILK is part of the same pathway as an important tumor-suppressor gene called PTEN. PTEN is mutated or not present in 60% of all human cancers, including those of the prostate, breast, colon, brain and lung. When PTEN is not functioning properly, ILK activity levels increase, and cells respond by growing at an uncontrolled rate, invading into new regions and sending out signals to encourage new blood vessel formation. "The combination of these cellular responses could account for the lethality of cancers caused by a mutation in PTEN," comments Dr. Dedhar.

Downstream of PTEN and upstream of the proteins that control tumor formation and growth, ILK is a key component of the integrin signaling pathway. ILK therefore represents an excellent therapeutic target for treating tumors associated with mutations in PTEN.

(Reference for initial discovery of ILK: Hannigan, G.E., et al., Nature, Vol. 379, January 4, 1996. To view article online: www.nature.com

What are ILK Inhibitors?

ILK inhibitors are small molecule drugs that bring the activity of ILK down to normal levels. In doing so, they provide a novel approach to prevent the growth and migration of tumors. Importantly, this therapeutic approach differs from conventional treatment options because it addresses the cause of disease rather than treating symptoms only.

Kinetek Pharmaceuticals (www.kinetekpharm.com) has developed several potential drug candidates that inhibit ILK, returning the enzyme's activity levels to normal and restoring the proper functioning of the integrin and growth factor signaling pathways. "When these pathways are working properly, cancer cells no longer receive the messages that trigger growth and invasion, and as a result, the cell has a limited survival time," explains Dr. Jasbinder Sanghera of Kinetek.

In preclinical research conducted by Kinetek scientist, Dr. Penny Costello and others, ILK inhibitors prevented cancer cells from migrating to new regions. The inhibitors stopped cancer cells from attaching to new sites and they prevented the growth of blood vessels and reduced the growth of tumors.

Unlike conventional cancer treatments, such as radiation and chemotherapy, ILK inhibitors do not simply target rapidly dividing cells. In preclinical studies, ILK inhibitors were shown to be well tolerated by healthy cells, functioning only to bring ILK activity of cancer cells down to normal levels.

Kinetek is currently in the process of optimizing its inhibitors to generate a compound that is ready for clinical trials in humans. Phase one clinical trials -- which assess safety and dose tolerance issues - should be underway within the next 24 months.

What is Signal Transduction?

Signal transduction is the process by which cells communicate with one another and their environment. Researchers are increasingly interested in signal transduction because it is clear that defects in components of signal transduction machinery lead to major diseases like cancer and diabetes.

"Signal transduction is often called the original Internet because of the sheer volume and complexity of messages that are sent and received by our cells," says Jasbinder Sanghera, Vice President of Drug Discovery at Kinetek Pharmaceuticals. "Messages are constantly passing in and out of the cell, triggering hundreds of biochemical reactions. These reactions control the key cellular processes that ensure our cells grow, reproduce, repair themselves, conduct specialized activities, and even die in an orderly and cooperative manner."

A class of enzymes called protein kinases act as key messengers in this cellular communication network. By relaying messages from the cell surface to the cell nucleus, protein kinases control and regulate gene expression and cell behavior in response to extracellular signals. For instance, if we cut ourselves, signals are sent into a skin cell to stimulate it to move into the damaged area to repair the cut tissue.

If the signaling process becomes altered, abnormal messages are received by the cell nucleus. Critical proteins are then either overproduced or underproduced, which can lead to improper cell behavior. Aberrations in the signaling pathway system have been shown to cause serious chronic diseases including cancer and diabetes, as well as cardiovascular and neurological disorders.

Two of the most important signal transduction pathways are the integrin and growth factor signaling pathways because these control cell growth, migration and blood vessel formation. Researchers have identified abnormalities in the components involved in both the integrin and growth factor signaling pathways. These components are defective in 60% of all human cancers. "Finding ways to correct these defective proteins," explains Dr. Sanghera, "could offer new treatment options for people with cancer."

For details, please contact:

David Roberts, Kinetek Pharmaceuticals (604-269-2255) droberts@kinetekpharm.com