Researchers from The University of Texas M. D. Anderson Cancer Center reported in the Journal of the National Cancer Institute ( JNCI ) that Imatinib, a medication used to treat other types of cancer, strangles drug-resistant, metastatic prostate cancer by cutting off its blood supply.

Imatinib, known commercially as Gleevec ( Glivec in Europe ), 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 successfully warded off the combined medications in lab experiments, said Isaiah J. Fidler, director of the Cancer Metastasis Research Center at M. D. Anderson.

Fidler and colleagues showed in the JNCI paper that Imatinib killed tumor-related endothelial cells by inactivating the platelet-derived growth factor receptors ( PDGFR ) 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 PDGFR 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 PDGFR, 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.

Earlier research by Fidler and colleagues showed PDGFR activation in metastatic prostate tumors adjacent to the bone but not in tumor cells next to muscle. PDGFR also was activated in tumor-associated endothelial cells in the bone, but not in those blood vessel cells in neighboring muscle.

A JNCI paper by Fidler and colleagues in 2003 showed that blocking PDGFR signaling in the mouse model of metastatic prostate cancer cut the incidence of cancer, reduced the size of tumors and incidence of metastasis.

Imatinib had an effect by itself, but the best result came from the pairing with Paclitaxel, known commercially as Taxol, which induces apoptosis in non-resistant cancer cells. Taxol is frontline therapy for prostate cancer but eventually loses its effect as resistant tumor cells proliferate.

Gleevec is used to treat chronic myelogenous leukemia and gastrointestinal stromal tumors.

Cancer cells are biologically diverse and genetically unstable, Fidler says, so it is highly unlikely that a single therapy will prevail, necessitating a multi-modal attack on the disease.

Source: University of Texas M. D. Anderson Cancer Center, 2006


XagenaMedicine2006