Measuring enzymes at end of cancer pathway predicts outcome of Tarceva, Taxol

04/13/05

ANAHEIM - Researchers at The University of Texas M. D. Anderson Cancer Center have developed a way to test whether the new targeted therapy Tarceva and the widely used chemotherapy drug Taxol are effectively killing tumor cells. They say that with further refinement, the test may make it possible to accurately assess whether patients are responding to these agents, as well as potentially others, within days of beginning therapy.

In two different studies being presented at the annual meeting of the American Association for Cancer Research (AACR), the research team will describe how the test measures the activity of several members of the cyclin-dependent kinase (CDK) family of enzymes, which are the triggering molecules that allow a cell to grow and divide. CDK cell cycle enzymes are the end target of numerous cellular pathways that are involved in cancer development and progression, the researchers say. Before these studies, no one has been able to accurately test the function of enzymes from a tumor sample, says Naoto Ueno, M.D., Ph.D., an associate professor in the Breast Cancer Translational Research Laboratory and the Department of Blood and Marrow Transplantation. "Testing CDK only has been possible by measuring gene expression, but our industry collaborator has provided a way that lets us test real enzyme activity within a human tumor sample," he says. "Our hope is to be able to use this system as a molecular marker to assess whether an anti-cancer therapy is working."

ABSTRACT # 1670

Sensitivity to Tarceva Depends on CDK2

In the first study, M. D. Anderson researchers found that loss of the CDK2 enzyme strongly correlated with a cancer's sensitivity to Tarceva.

That means testing activity of CDK2, the enzyme that drives cell division, can reveal whether or not a tumor will respond to Tarceva, says Naoto Ueno, M.D., Ph.D., an associate professor in the Breast Cancer Translational Research Laboratory and the Department of Blood and Marrow Transplantation. If results of this study are verified and validated, "a CDK2 test would provide the best marker yet for effective use of Tarceva," he says. The only experimental predictive test currently available is whether lung cancer cells have a mutation in their epidermal growth factor receptor (EGFR), but that does not predict response to the targeted therapy in other forms of cancer, Ueno says.

"We find here that as long as CDK2 is suppressed, the drug works, so developing an accurate test for CDK2 activity would be a boon for delivering individualized therapy to patients," he says. Such a test, however, will require that patients be given the drug for a short period of time so that the agent's effect on CDK2 activity can be assessed.

In this study, the researchers exposed 10 different human breast cancer cell lines to varied doses of Tarceva and then measured activity of the CDK enzymes. They found that tumor cell death was significantly dependent on whether CDK2 activity was repressed. They then double checked those findings by "putting CDK2 back," Ueno says. "We found that the effects of Tarceva were reduced when CDK2 was given back to the cells, so this shows us that CDK2 is the real target of Tarceva.

"This presents a concept that describes how Tarceva works, and it also shows that we have a technology that can rapidly measure the true activity of CDK2 in a tumor sample," Ueno says. First author Fumiyuki Yamasaki, M.D., Ph.D., a post-doctoral fellow, is presenting the findings at AACR.

ABSTRACT # 459

Profile CDK to Predict Effectiveness of Taxol

A different research team, headed by Naoto Ueno, M.D., Ph.D., an associate professor in the Breast Cancer Translational Research Laboratory and the Department of Blood and Marrow Transplantation, found in a second study presented at AACR that if activity of several CDK molecules is increased - not decreased as in the Tarceva finding - then the chemotherapy drug Taxol appears to effectively kill breast cancer cells.

Taxol, used to treat a wide spectrum of cancers, works by interrupting the reorganization of the cell that is necessary if it is to divide. While it was known that the primary effect of the drug is to interfere with assembly of the spindle that pulls nuclear chromosomes apart during cell division, Ueno and his colleagues have recently reported that increased activity of CDK1 correlated with a cell's sensitivity to Taxol.

The CDK enzyme plays a role in cell division, and researchers believe that it functions in part as a monitor of cell cycle activity. Ueno theorizes that if something goes wrong during division - such as if Taxol is interrupting spindle assembly - CDK will become more active in an attempt to correct the problem.

Working with the Sysmex Corporation of Kobe, Japan, the researchers devised a test to measure CDK activity and the expression, simultaneously.

They found that monitoring of two isotypes of CDK activity accurately predicted which tumors would respond to Taxol in the experiments with human breast cancer cell lines and tumor tissues of human xenograft model.

"This provides solid preclinical evidence that we can use toward development of a novel device that can measure CDK activity in human tissue within several hours," Ueno says. He adds that a clinical trial is currently under way that tests CDK activity both before and after patients with breast cancer are treated with Taxol.

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