A new prospective study involving 188 adult patients with acute myelogenous leukemia (AML) has demonstrated what many researchers had suspected but not necessarily proven: In cancer cells, multiple intracellular signal transduction pathways that affect functions such as cell death and proliferation are simultaneously activated. Beyond that, however, was a more unexpected finding: The more of these pathways that are activated, the worse a patient's prognosis.

The findings, say the research team that conducted the study, strongly suggest that when one of these pathways is activated as a result of a genetic mutation or some other mechanism, other important signaling pathways that influence cancer cell development and proliferation - pathways that would typically be static or only mildly active in a normal bone marrow or white blood cell - also become activated, often referred to as "crosstalk."

One other finding, said the study's lead author, Dr. Steven M. Kornblau from the University of Texas M.D. Anderson Cancer Center, further supports this contention.

"We found that patients were far more likely to have all of [the pathways] turned on, or none turned on," Dr. Kornblau explained. "That was pretty good evidence for crosstalk."

Evidence of extensive crosstalk could have significant implications for the development of new targeted treatments for AML and possibly other cancers, he argued. If a compound only inhibits a single target in one of these pathways, the other pathways can continue to fuel the cancer.

"There's a lot of redundancy in these pathways and a lot of ways to get from point A to point B," Dr. Kornblau said.

Published in the October 1 issue of the journal Blood, the results may help explain what many researchers have considered a substandard performance of the molecularly targeted agents already in clinical use, said Dr. Jerry Radich of the Fred Hutchinson Cancer Research Center.

"This underlines what we've suspected for a while," he said. "Within a cell there is a complicated system of checks and balances, and to become a leukemia cell so many things have to go wrong…that it will be very difficult to target one unique pathway and kill all of the cells."

Dr. Kornblau and his colleagues conducted the study by analyzing peripheral blood or bone marrow samples from patients with newly diagnosed AML being treated at M.D. Anderson between 1999 and 2004. The team focused their analysis on the signaling pathways - PKCα, RAS/Raf/MEK/ERK, and PI3K/AKT - that they and others have previously identified as being highly active in AML patients.

Activation of each individual pathway correlated not only with overall survival, but also with the ability to achieve complete remission and remission duration.

To overcome this crosstalk, said Dr. Kornblau, increased cooperation between industry and academic investigators to conduct studies and clinical trials that test several agents with different targets is desperately needed.

Dr. Radich agreed. "It's going to take a change in how investigators, pharmaceutical companies, and the FDA look at these things," he said.

To date, intellectual property and regulatory hurdles have made it very difficult to conduct such studies, Dr. Kornblau said.

But according to Dr. James Zwiebel, acting chief of NCI's Investigational Drug Branch, NCI is making progress in this area. "We have executed agreements with industry collaborators that have allowed combinations of investigational agents in both preclinical studies and clinical trials," he said.

NCI's Cancer Therapy Evaluation Program is currently sponsoring approximately 130 clinical trials of investigational agent combinations, he added, compared with approximately 15 such trials in 2000.

By Carmen Phillips