Scientists Seek to Establish Model of Prostate Cancer Dormancy

JERUSALEM--Tumor cells that are not eradicated by chemotherapyor radiotherapy can enter a prolonged dormant state and thus posea continuous threat of tumor relapse in patients who are seemingly"cured," Eitan Yefenof, PhD, said in an interview withOncology News International.

Although there is evidence that prostate cancer cells can entera prolonged quiescent period following therapy, little is knownabout the mechanism underlying the induction and maintenance ofthis dormant state.

Dr. Yefenof, of the Lautenberg Center for General and Tumor Immunology,Jerusalem, and his colleagues at the University of Texas SouthwesternMedical Center, Dallas, led by Dr. Jonathan Uhr, have taken thefirst step toward understanding the dormant state in prostatecancer with their project to establish an experimental model ofhuman prostate cancer dormancy in nude mice.

"Very little is known about the biology of dormant tumorcells and the cellular and molecular mechanisms that lead to thedormant state," Dr. Yefenof said. "We are studying themto see what kinds of genetic mutations are causing the dormantstate and how the dormant state can be terminated, eradicated,or kept silent for an extended period so as not to evoke clinicalmanifestations in the host."

Much of what is known about dormant tumor cells comes from workdone by Dr. Yefenof when he was a visiting professor at UT Southwesternin 1993. "We developed an experimental model for tumor dormancyusing lymphoma cells. We think what we learned about the dormantstate from this model can be applied to carcinomas as well."

Dr. Yefenof believes that dormant tumor cells still have a malignantgenotype, but receive a growth inhibitor signal from the environmentthat prevents their proliferation. The dormant cells may suddenlybecome active if the inhibitory signal is somehow "turnedoff" or if the cell itself develops "resistance"to the signal.

"If the countermanding signal is removed, the cells willregrow and produce a tumor," Dr. Yefenof said. Alternatively,the dormant cells may acquire an additional mutation that rendersthem insensitive or resistant to the external signal that hadbeen keeping them under check.

"So now you have a new tumor genotype that does not respondto the countermanding signals. It will grow and produce a tumorthat will be much more aggressive than the primary tumor becauseit has acquired an additional mutation," he said.

Potential Therapeutic Approaches

These theories suggest possible therapeutic interventions. Thefirst approach would be to develop modalities to eradicate dormanttumor cells, but this is difficult to do since dormant cells arenot dividing and thus do not respond to conventional chemotherapy.

Dr. Yefenof suggested that immuno-toxins, a toxin coupled to anantibody, could overcome this difficulty. An antibody that recognizesa particular antigen expressed only on malignant cells would directthe toxin to the malignant cells, allowing the toxin to penetrateand kill the cells even if the cells are not dividing.

To overcome "resistant" tumor cells, Dr. Yefenof hopesto develop antigen ligands that would bind to specific surfacereceptors and induce growth inhibitory signals. "The malignantcells would receive this external countermanding signal and stopdividing," he said.

In the lymphoma studies in Dallas, Drs. Yefenof and Uhr were ableto induce a dormant state by delivering an antibody that interactswith the surface immunoglobulin receptor expressed on a particularB cell lymphoma. When the surface immunoglobulin receptors wereoccupied by antigen ligands, the B cells often responded withgrowth inhibition and cycle arrest, he said.

"Rather than killing these cells, you stop their divisionand make sure that they remain dormant for as long as possible,"he said. "You don't cure the patient because the malignantcells are still there, but you depress their continuous proliferationand growth, thus avoiding clinical manifestations of disease."