For decades, cancer treatments were largely "one size fits all." Recently, however, powerful new technologies have enabled researchers to identify specific molecular pathways and processes within cells that cause cancer to grow, recur, and respond to or resist treatment. The best hope for improving cancer treatment outcomes in the future, many researchers believe, rests on the ability to tailor therapy to the specific molecular and biochemical characteristics of individual patients' tumors.

Research presented at the annual meeting of the American Association for Cancer Research highlighted a new technology developed by U.S. government researchers that takes a major step toward individually tailoring cancer treatment based on a "snapshot" that reveals the entire pattern of protein activity in a patient's tumor.

"Our goal is to improve the effectiveness of cancer treatment by identifying which patients are likely to respond to particular therapy based on individual profiles of protein activity," explained Emanuel Petricoin, Ph.D., co-director of the Clinical Proteomics Program, a joint venture of the U.S. Food and Drug Administration (FDA) and the National Cancer Institute (NCI).

Multiple genetic mutations are the underlying cause of most cancers. But the reason these defective genes cause cancer is that they encode abnormal proteins that, either directly or as a result of interaction with other proteins, stimulate or fail to suppress the uncontrolled growth of cancer cells.

"This new technology enables us to look directly at the proteins in the patient's tumor, identify which ones are activated, and observe the effects of treatment on protein interaction," he said. "We can glean this information from a tiny sample of tumor tissue that amounts to about a hundred cells."

Petricoin and his colleagues expect to be able to use this information soon to select the initial therapy most likely to be effective for a patient, monitor the patient's response to therapy, figure out what went wrong if the cancer recurs, and choose another therapy or combination of therapies that targets the abnormal protein pathway responsible for the recurrence.

The researchers are currently testing the technology with several clinical collaborators in patients with breast and ovarian cancer who are taking part in a clinical trial at the National Institutes of Health (NIH) in Bethesda, Maryland. In collaboration with the NCI, the Clinical Proteomics Program is analyzing patients treated with the drug trastuzumab (Herceptin®), followed a month later by the drug paclitaxel (Taxol®).

After analyzing the protein "profiles" of about 20 patients to date, the investigators noted a distinct difference in patients who respond to the therapy and those who don't. In responders, trastuzumab seems to reduce activation of a protein called Akt, which is involved in sending signals that suppress apoptosis in cancer cells, or programmed cell death. In non-responders, however, trastuzumab was found to have no effect on Akt.

"We think that in the responders, Herceptin is reducing activation of Akt, which destroys the signaling pathway that tells cancer cells to survive," said Petricoin. "When the patients receive Taxol, that drug throws the cells into apoptosis. But in the non-responders, the pro-survival signals remain intact and the cancer cells refuse to die even when Taxol is given."

The new protein analysis technology brings together two technological advances. The first, known as Laser Capture Microdissection, enables the rapid dissection of cancer cells directly from a patient's tumor specimen. The second, known as a protein reverse phase lysate microarray, makes it possible to analyze a thousand proteins on a single laboratory slide.

Petricoin and his colleagues are continuing to test the technology in more patients in the breast and ovarian cancer trial as well as in other trials that are just now beginning accrual to evaluate new molecularly targeted drugs such as STI571 (Gleevec™) and ZD1839 (Iressa®).

SOURCE:
93rd Annual Meeting of the American Association for Cancer Research, April 8, 2002, San Francisco, CA