By Malorye A. Branca
July 14, 2004 | They came hoping for news about “smart bombs,” “silver bullets,” and “rational” therapies that would help them improve some of cancer’s most pathetic cure rates. But if oncologists at this year’s American Society for Clinical Oncology (ASCO) meeting* learned anything, it was that the path to targeted cancer therapy is by no means clear.
Drugs thought to be highly targeted can still have multiple effects, and many work by means other than their intended mechanisms. For example, one ASCO speaker presented evidence that Gleevec -- Novartis’ wonder drug targeting the infamous Philadelphia Chromosome mutation -- also works as an inhibitor of tumor blood vessel growth.
Doug Hanahan, of the University of California at San Francisco, described animal studies combining Gleevec with another compound - Pfizer’s SU5416. The combination shrank tumors, and the group’s molecular studies suggest Gleevec can slow tumor blood vessel growth by picking off important cells called pericytes. Most important: “The treatment is not pulling the pericytes off the normal vessels,” Hanahan said.
Its not year clear why normal blood vessels are spared, but the combination works better by hitting different points in the blood vessel formation pathway. Hanahan suggested Gleevec should be tested with other angiogenesis inhibitors, and these studies should not be limited to tumors that express the drug’s traditional targets -- cKIT, BCR-ABL, or PDGFR.
Show Me the Target
Gleevec is the result of about two decades of research, so it is both inspiring and unnerving that the drug’s effects are still being worked out. And this is only one of several targeted therapies that has shown surprising unanticipated effects.
The key to understanding how these new drugs really work, and the best ways to combine them in patients, may lie in the hands of diagnostic test developers like Dako Cytomation.
Dako makes the Her-2 test that was approved in tandem with Genetech/Roche’s Herceptin, it has also recently released a test for the EGFR receptor. The Dako test was used in clinical trials of AstraZeneca’s Iressa and ImClone’s Erbitux, both of which target EGFR. Dako’s test is being used to guide prescribing of Erbitux, but not for Iressa, because it did not help predict which patients respond to that drug.
“What’s starting to emerge, is that the activation state of the receptor isn’t always the most important factor,” says Dennis Chenoweth, corporate vice president of diagnostics for DakoCytomation. In some cases, he explains, matching patients to drugs may require measuring, “A combination of receptor expression on cell surface, signal transduction proteins, and various levels of activation.”
Dako already uses multiple reagent tests in some of its collaborations, and Chenoweth predicts further advances as, “We get more sophisticated digital analysis capability.” Most pathology slides are currently read by pathologists. As more features are studied per slide, however, computerized image analysis will become the norm.
But companies aren’t waiting for the fancier technology. “Everybody is doing this kind of testing in clinical trials [for targeted cancer drugs],” Chenoweth says. “Because at some point, the regulatory agency will say ‘Show me the data.’” Dako has programs with almost every major pharmaceutical company, he says, and “This is a very interesting part of our business and our strategic plan.”
*ASCO, June 5-8, New Orleans