Molecular Pathway May Predict Chemotherapy Effectiveness

CincinnatI—A common molecular pathway could help physicians predict which lung cancer patients will benefit from chemotherapy drugs, according to new research from a multidisciplinary team at the University of Cincinnati (UC).

Known as the retinoblastoma (RB) tumor suppressor, this fundamental molecule regulates cell proliferation in the body. Research has shown that the RB pathway is either entirely inactive or altered in most human cancers. Scientists are beginning to use its actions as a “biomarker” for how tumors will respond to different therapies.

Michael Reed, MD, and his UC colleagues found that “turning off” the RB pathway in lung cancer cells resulted in an altered response to chemotherapy agents and more cancer cell death. They report their findings in the September 2007 issue of the journal Cancer Research.

“Dissecting the RB pathway will help us better understand how chemotherapy works and predict which patients might benefit from therapy and which ones won’t,” explains Reed, assistant professor of surgery at UC and a thoracic surgeon at University Hospital.

“As pathways are further defined, we could choose agents that are targeted to an individual tumor’s molecular characteristics,” he adds.

A previous UC study, published in the January 2007 issue of the Journal of Clinical Investigation, showed that when this pathway is disrupted or shut off in breast cancer, the tumor resists anti-estrogen drugs and the cancer continues to grow in spite of the therapy.

For this laboratory study, Reed’s team shut off the RB pathway in human non-small cell lung cancer cells and exposed them to chemotherapy agents representative of those currently used to treat lung cancer patients.

Their results showed that when RB was turned off, the cancer cells continued to divide, but became more susceptible to the drugs, so the tumors stopped growing.

“But the minute you take away the chemotherapy, the cells take off again,” says Reed. “This suggests that it’s not just loss of RB that affects therapy response—it could be changes at various steps in cellular signaling that result in different outcomes.”

“The traditional way of thinking of cancer—one cancer gene to treat and you’re done—is obviously not the best approach to treating this disease,” he adds. “These are complex, overlapping molecular pathways. Dissecting them and determining how to use that information to apply combinations of chemotherapeutic agents will allow for individualization of therapy.”

Next year, Reed and his colleagues expect to begin testing the RB tumor suppressor in human tumor tissue samples from the UC Thoracic Tumor Registry and compare them to patients with known outcomes.

According to the American Cancer Society, more than 213,000 Americans will be diagnosed with lung cancer in 2007. Because most people are diagnosed late, the five-year survival rate is only 14 percent—compared with 86 percent for breast cancer, 61 percent for colon cancer and 96 percent for prostate cancer.

This study was funded by a grant from the National Institutes of Health and UC College of Medicine Dean’s Discovery Fund and the UC cancer research program. UC study collaborators include Erik Knudsen, PhD, and William Zagorski.