Gleevec strangles drug-resistant, metastatic prostate cancer

A medication used to treat other types of cancer strangles drug-resistant, metastatic prostate cancer by cutting off its blood supply, researchers from The University of Texas M. D. Anderson Cancer Center report in the June 7 issue of the Journal of the National Cancer Institute.

Imatinib, known commercially as Gleevec, worked best when combined with the chemotherapy paclitaxel to slash the incidence of bone metastases and the size of tumors in mice injected with a multiple-drug resistant form of prostate cancer. Tumors were found in only 4 of 18 mice treated with the combination, median tumor weight was one tenth of a gram, and the cancer spread to the lymph nodes in three cases. Tumors grew in all 19 control mice, their median tumor weight was 1.3 grams, and all metastasized to the lymph nodes.

This extremely drug-resistant form of the cancer, designed by the research team to emulate the grim clinical reality of prostate cancer that has spread into the bone, successfully warded off the combined medications in lab experiments, said Isaiah J. Fidler, D.V.M., Ph.D., chair of the Department of Cancer Biology and director of the Cancer Metastasis Research Center at M. D. Anderson.

"Why, then, did it work so well in the animal? Because we didn't attack the tumor, we attacked the blood vessels. We target and destroy the vasculature that provides oxygen and nutrients to tumor cells," said Fidler, the paper's senior author.

Fidler and colleagues show in the JNCI paper that imatinib killed tumor-related blood vessel (endothelial) cells by inactivating the platelet-derived growth factor receptors (PDGF-R) on the cell surface. This prevents the receptor's activation either by PDGF binding to it externally or by a signal generated internally by the cell.

Activation of PDGF-R stimulates the birth of new blood vessels, promotes cell division and migration, and inhibits a protective form of cell suicide known as apoptosis, all harmful effects in the service of a cancer cell.

With imatinib preventing activation of PDGF-R, Fidler said, the endothelial cells died by apoptosis first, with tumor cells following suit one to two weeks later.

Fidler said the findings are a vibrant example of the "seed and soil" hypothesis in metastasis - the deadly spreading of a cancer from its organ of origin to other organs, a process that kills 90 percent of all patients who die from their disease.

In landmark findings, Fidler and colleagues demonstrated that the vast majority of cancer cells that depart a tumor die swiftly once in circulation and that metastases originate from less than 1 percent of a cancer's cells and even can arise from a single cell.

When these metastatic "seeds" enter circulation, they still need to find the exact microenvironment that permits them to grow. For prostate cancer, the second-leading cause of cancer death among men, that microenvironment is the bone.