Gleevec Attacks Prostate Cancer in Mice

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Univ Of Texas - MD Cancer Center

July 2006

Gleevec Attacks Prostate Cancer in Mice

Drug Works by Destroying Tumor's Blood Supply

Imatinib (GleevecR), which has been successful in treating some

leukemias and gastrointestinal stromal tumors (GIST), stopped the growth

of prostate cancer that had spread in mice, according to a report in the

June 7 issue of the Journal of the National Cancer Institute.

M. D. researchers tested Gleevec by first injecting two groups

of mice with a chemotherapy-resistant form of prostate cancer. One group

received a combination of Gleevec and paclitaxel (TaxolR). The second

group did not receive treatment.

Fewer tumors and less metastasis in Gleevec group

In the group given the Gleevec combination:

a.. Tumors were found in only 4 of 18 mice

b.. Median tumor weight was one-tenth of a gram

c.. Cancer spread to the lymph nodes in three cases

In the control group not given the combination:

a.. Tumors grew in all 19 mice

b.. Median tumor weight was 1.3 grams

c.. Cancer spread to the lymph nodes in all mice

Gleevec succeeds by cutting off tumor's blood supply

The research team used an extremely drug-resistant form of prostate

cancer, which they designed, to emulate the grim clinical reality of

prostate cancer that has spread into the bone, says Isaiah Fidler,

D.V.M., Ph.D., chair of M. D. 's Department of Cancer Biology

and director of the Cancer Metastasis Research Center at M. D. .

" Why, then, did it work so well in the animal? Because we didn't attack

the tumor, we attacked the blood vessels, " says Fidler, the paper's

senior author. " We target and destroy the vasculature that provides

oxygen and nutrients to tumor cells. "

In their report, Fidler and colleagues show that Gleevec killed

tumor-related blood vessel (endothelial) cells by inactivating the

platelet-derived growth factor receptors (PDGF-R) on the cell surface.

Activation of PDGF-R:

a.. Stimulates the birth of new blood vessels

b.. Promotes cell division and migration

c.. Inhibits apoptosis, a form of cell suicide

All are harmful effects that fuel growth of cancer cells.

With Gleevec preventing activation of PDGF-R, Fidler says, the

endothelial cells died by apoptosis first, with tumor cells following

suit one to two weeks later.

Additional therapies needed for advanced cancer

Fidler said the findings are a good example of the " seed and soil "

hypothesis in metastasis - the deadly spreading of a cancer from its

organ of origin to other organs. This process kills 90% of all patients

who die from their disease.

Gleevec had an effect by itself, but the best result came from the

pairing with Taxol, which induces cell death in non-resistant cancer

cells. Taxol is frontline therapy for prostate cancer, but eventually

loses its effect as resistant tumor cells proliferate.

Cancer cells are biologically diverse and genetically unstable, Fidler

says, so it is highly unlikely that a single therapy will prevail. This

necessitates multiple modes of attack on the disease.

Gleevec has been effective in treating chronic myelogenous leukemia and

GIST and is being studied as a treatment for other cancers.

- From staff reports

Resources:

Isaiah Fidler, D.V.M., Ph.D.

Department of Cancer Biology