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Researchers hope to go after molecular targets, not cancers.

By Deborah Borfitz

Feb. 1, 2008 | Do cancer patients respond better to an onco-genomic guided therapy than a doctor’s “educated guess?” Results of a landmark molecular profiling study will provide the answer and, if it’s yes, will likely spur interest in the concept as a way to increase treatment success while lowering development time and expense, says Stephen Anthony, director of TGen Clinical Research Services at Scottsdale Healthcare in Arizona.

The $6 million project is sponsored by TGen (Translational Genomics Research Institute) and Scottsdale Healthcare, the company’s clinical unit, and funded through an endowment from the Stardust Foundation. The molecular profiling study began in September 2006 and patient accrual will be completed by the first quarter of 2008, says Anthony.

Based on genetic information from tumor tissue samples and immunohistochemistry stains (for localizing proteins in cancer cells), investigators will select a molecular directed therapy, says Anthony. “Potentially, that will guide us to use a leukemia drug to treat patients with breast cancer. It will force us to think outside of the box because we’re going after a molecular target and not a type of cancer.”

Anthony, a hematologist and medical oncologist, says all of the patients he sees at Scottsdale Healthcare are “highly refractory to conventional treatment. Patients have to be qualified to go into clinical trials because that’s all we offer here.”

The focus of TGen is to develop targeted therapies and it has “strong genomic capabilities to carry out the mission,” says Anthony. Already, more than a quarter of the 400 oncology drugs under development are on the “radar screen” of TGen, one of the few non-academic centers working to accelerate drug development for cancer patients.

Five-year-old TGen does all the basic science work at a facility in downtown Phoenix (opened in December 2004) and all Phase I clinical trial work gets done at Scottsdale Healthcare, says Anthony. TGen is particularly adept at “enrichment” of patient populations for clinical trials, by homing in on patients likely to have the target a compound is designed to attack, says Anthony. Herceptin, for instance, is given differentially to breast cancer patients who have too many copies of the HER2 gene and express the HER2 receptor.

If an oncology drug gets through a first-in-man trial and looks promising, TGen partners with other large cooperative oncology groups, such as U.S. Oncology and Southwestern Oncology Group, to participate in later-stage trials. In response to growing interest in targeted therapies among drug developers and the general public, TGen is considering adding a second clinical site outside the state of Arizona in the second half of 2008, he says.

Protein Tracking
A majority of trials done by TGen involve measuring the level of protein in a cancer cell, not looking at all 22,000 genes in fresh tumors, as is the case with the landmark molecular profiling study now underway. “If you see a clear expression at the gene level, and…the expression of that gene at the protein level, then you’re looking at a protein specific-driven cancer cell, and it’s appropriate to use a therapy directed at that protein or molecular target,” says Anthony.

Cancer is a heterogeneous disease, says Anthony. “On a good day, 30 to 40 percent of [existing] therapies work.” Better results come from treatments based on patients’ unique genetic signatures. Cambridge, UK-based KuDOS Pharmaceuticals (a wholly owned subsidiary of AstraZeneca), for instance, has shown that women with faulty genes BRCA1 and BRCA2 have a “dramatic response” to treatment with a poly (ADP-ribose) polymerase inhibitor.

“Within the last year, in particular, there has been a progressive swing toward molecular targeted therapies in oncology drug development,” says Anthony. Still, not everyone has bought into the concept.

Some companies prefer to start with conventional drug development, since the FDA threshold for approving oncology drugs is only a 10 percent positive response rate. They may then test a molecular targeted therapy to tease out why the drug worked so well on that minority, says Anthony.

In the field of molecular medicine, the biggest technological need is in the arena of computational biology because of the sheer number of factors that can impact cancer-causing genetic mutations, says Anthony. “The need to find definitive therapies that accurately target and eliminate disease while not harming the patient will require a critical understanding of the myriad networks of communication that cancer cells possess. With greater understanding of these pathways, we can offer patients what they have always wanted, and that is more quality time with their family and friends.”

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This article appeared in Bio-IT World Magazine. 
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