Redirecting Localization of the Prostate-Specific Membrane Antigen for Therapeutic Targeting

Abstract

Using a common chemotherapy agent, researchers at UCLA's Jonsson Cancer Center and the Department of Pathology and Laboratory Medicine found a way to move an important biomarker expressed in prostate cancer, shaking it loose from one location in a cell - where it could not be accessed by blood - to another, easier to target area.

The discovery, outlined in the cover article of the May 11, 2005 edition of the journal Molecular Cancer Therapeutics, could have important implications for using immunotherapy to treat prostate cancer, said Ayyappan K. Rajasekaran, a Jonsson Cancer Center researcher and senior author of the article.

The method discovered by the research team places the prostate-specific membrane antigen (PSMA) in a location on the cell that would allow blood-borne immunotherapies to access the biomarker, transforming it from a hidden target into an exposed one.

"In prostate cancer cells, PSMA is expressed in the apical region of the cell membrane, which blood can't reach, so injection of immunotherapy into the bloodstream is not effective," said Rajasekaran, also an associate professor of pathology and laboratory medicine. "By using information from very basic studies about how the PSMA protein is targeted in these cells, we identified a way to redirect this protein within the cell. We found that if we disturbed hollow tubular structures called microtubules, part of the cell's framework, we were able to relocate PSMA from its 'hidden' location on the apical membrane to an accessible area in the basolateral surface."

To cause this disturbance and the resulting relocation of PSMA, Rajasekaran and his team employed a commonly used cancer chemotherapy agent, which destroys the microtubules.

"These patients are getting chemotherapy anyway, and once we move the PSMA to a more accessible area on the prostate cancer cell, we might be able to use antibody-based immunotherapies as well, and they could be administered in the blood," he said.

Rajasekaran said PSMA is an important biomarker for prostate cancer and its expression in the cell is proportional to the severity of the cancer - the more advanced the disease, the more PSMA is expressed.

Rajasekaran and his team also showed for the first time in this study that prostate cancer cells maintain a well-differentiated morphology, with the PSMA hidden in the apical membrane of the cell, even when the cancer spreads outside the prostate - a fact that hadn't been proven before. Many researchers, in fact, had believed the opposite was true, Rajasekaran said. So discovering the mechanism of moving the PSMA to a more treatment accessible location on the cell could have ramifications for treating the sickest patients, those in whom the cancer has spread.

"The ability to reverse the polarity of PSMA from apical to the basolateral could have significant implications for the PSMA as a therapeutic target," the study states.

Pairing treatments may be even more important for patients with advanced cancers, for whom few options are available, Rajasekaran said.

"Chemotherapy alone doesn't do everything and immunotherapy alone might not do everything, but if could use both, we might have more success in treating patients, especially those whose cancer has spread," he said.

Rajasekaran and his team performed their research in prostate cancer cells lines and plan to validate their findings first in animal models and then in human clinical trials, which could be available in three to four years.

Prostate cancer is expected to strike 232,090 men this year alone, according to the American Cancer Society. Of those, 30,350 are expected to die. Prostate cancer is the second leading cause of cancer death in men.

UCLA's Jonsson Comprehensive Cancer Center is made up of more than 240 cancer researchers and clinicians engaged in cancer research, prevention, detection, control, treatment and education. One of the nation's largest comprehensive cancer centers, the JCCC is dedicated to promoting cancer research and applying the results to clinical situations. In 2004, the Jonsson Cancer Center was named the best cancer center in the western United States by U.S. News & World Report, a ranking it has held for five consecutive years.