Researchers study Rituximab's action on cancer stem cells

Preliminary data from one of the first clinical trials to test a stem cell-targeting drug in cancer patients shows that while the drug did not prolong survival, its suppressing effect on patients' stem cells was impressive enough to send investigators looking for a better drug to try.

As an emerging field of study in cancer research, stem cells are believed to sprout cancer much like the hidden roots of weeds that elude efforts to get rid of them.

Rituximab, a drug currently approved to treat B-cell lymphomas, plus a common chemotherapy agent, cyclophosphamide, were given to 21 patients whose multiple myeloma, a cancer of the bone marrow, had relapsed or was defined as high-risk first remission. A previous study using the drug alone in multiple myeloma patients suggested that the disease in some participants progressed more slowly.

During the study, the Johns Hopkins team examined the stem cells under the microscope. “We found cancer stem cells coated with rituxumab, but the drug wasn't killing them,” said Carol Ann Huff, M.D., assistant professor of oncology. “We think the idea is correct, but the drug itself wasn't the right one.” Rituximab is sold under the trade name Rituxan.

Huff and her team believe that several therapies are required to kill cancer - one to get rid of the bulk of the tumor, like mowing the lawn, and another to hit the root of the cancer, its stem cells. “We think one reason that cancer comes back is because stem cells, which are resistant to chemotherapy, repopulate the body with new cancer cells,” says William Matsui, M.D., assistant professor of medicine at the Johns Hopkins Kimmel Cancer Center.

Their test of the rituximab-cyclophosphamide combo showed up to a 1000-fold reduction in cancer stem cells during the initial treatment. However, stem cell quantities eventually crept back up and led to a progression of disease. Investigators were able to predict when patients' disease would recur by tracking the number of stem cells they had. The average advance notice was two months.

Since the study began in early 2005, four patients have died from their disease, three remain progression-free, and the rest have disease that has progressed.

Matsui and Huff are currently testing drugs that block an enzyme called telomerase, which may give cancer stem cells longevity, and other drugs that block a stem cell-signaling pathway called hedgehog. Other promising therapies, according to the scientists, include a combination of the drugs, interleukin-6 and interferon-alpha, which may prematurely age stem cells.

Funding for the study was provided by the National Cancer Institute, American Society of Clinical Oncology, the Commonwealth Foundation, and Genentech. In addition to Matsui and Huff, these Johns Hopkins scientists participated in the study: Q Wang, K Rogers, M Jung, Javier Bolanos-Meade, Ivan Borrello, and Richard Jones.