Mayo Clinic Researchers Find Oncogene is Important in Pancreatic Cancer Growth and Spread

Researchers at the Mayo Clinic campus in Florida have found that PKC-iota (PKCi), an oncogene important in colon and lung cancers, is over-produced in pancreatic cancer and is linked to poor patient survival. They also found that genetically inhibiting PKCi in laboratory animals led to a significant decrease in pancreatic tumor growth and spread.

The discovery, reported in the March 1 issue of Cancer Research, is especially encouraging, they say, because an experimental agent that targets PKCi is already being tested in patients at Mayo Clinic.

"This is the first study to establish a role for PKCi in growth of pancreatic cancer, so it is exciting to know that an agent already exists that targets PKCi which we can now try in preclinical studies," says the study's senior investigator, Nicole Murray, Ph.D., of the Department of Cancer Biology.

The drug, aurothiomalate, is being tested in a phase I clinical trial in patients with lung cancer at Mayo Clinic's sites in Minnesota and Arizona. Based on findings to date, a phase II clinical trial is being planned to combine aurothiomalate with agents targeted at other molecules involved in cancer growth.

Mayo Clinic researchers, led by Alan Fields, Ph.D., chair of the Department of Cancer Biology and a co-author of this report, discovered aurothiomalate in 2006 by screening thousands of Food and Drug Administration-approved drugs for their ability to inhibit PKCi signaling. The drug was once used to treat rheumatoid arthritis.

Dr. Murray stressed that this new study has not tested aurothiomalate against pancreatic cancer yet, but any treatment that targets this major cancer pathway offers a new avenue for therapy. "This is such a deadly disease. No standard treatment has shown much promise," she says. "New ideas and fresh, targeted therapies such as this are sorely needed."

Mayo researchers have led the field in understanding the role of the protein kinase C (PKC) family of enzymes as major players in cancer development and progression. Dr. Fields was the first to discover that PKCi is a human oncogene — an abnormal gene that cancer cells use to grow and/or survive. He found that PKCi is genetically altered and over-expressed in a majority of lung cancers, and that over-expression of the gene in tumors predicts poor patient survival. That led to his search for aurothiomalate and the current testing in patients.

Dr. Murray says she has also found that different members of the PKC family play distinct roles in colon cancer, which offers more opportunity for targeted treatment. In fact, animal studies show that use of a different drug, enzastaurin, significantly reduced the initial development of colon tumors, according to Dr. Murray. Enzastaurin targets PKC-beta (PKCb), which the Mayo team has shown is necessary for initiation of colon cancer, she says.

In the present study, the researchers looked at expression of PKCi in pancreatic cancer because tumor studies show that a different gene, KRAS, is mutated up to 90 percent of the time, and KRAS regulates PKCi. "KRAS has been very difficult to target therapeutically, which is why we are looking at molecules, such as PKCi, that convey signals downstream of KRAS that can be manipulated," Dr. Murray says.