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AstraZeneca to Develop Astex PKB Inhibitors; Compounds May Rescue EGFR-Drug Response

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In an agreement with AstraZeneca, UK-based Astex Therapeutics will provide the pharmaceutical giant with a set of drug candidates that inhibit protein kinase B, and may well be capable of recovering tumor response to EGFR inhibitors in patients for whom drugs like Genentech's Tarceva or AstraZeneca's Iressa are no longer effective.

Companies often look for effective drug combinations, said Neil Thompson, vice president of biology at Astex. "In this particular case, there is quite a strong argument to do so — in combination with things like Iressa and Tarceva, and maybe some cytotoxics. [T]he reason [is] that a lot of non-clinical data have been, for a number of years now, indicating that tumor cells growing in culture can be resistant to existing agents," such as EGFR-inhibiting drugs, he said. "That correlates very closely with an over-activation of PKB."

Inhibitors of PKB may prove to be effective cancer drugs in their own right, but drug makers are not likely to ignore the chance that they may be even more effective in combination with an EGFR inhibitor. Tumors often become resistant to EGFR inhibitors by re-activating the EGFR pathway, some of them by activating PKB. Supposing the combination is effective, treatment using an EGFR inhibitor may simply resume with assistance from the new drug. Detection of activated PKB might also require a diagnostic.

In June, Pharmacogenomics Reporter reported on research led by David Stokoe, an assistant professor who studies the EGFR pathway at the Cancer Research Institute of the University of California, San Francisco. The research showed that, among a group of 41 glioblastoma patients, those testing positive for EGFR protein expression and negative for activated PKB had slightly more than a 50-percent chance of responding to Tarceva. Patients who tested positive to activated PKB did not respond to the drug.

There are no PKB inhibitors on the market right now, partly because they are very difficult to develop, Stokoe said. "I think there [are] a lot of people working on them," including Merck, Schering Plough, and Keryx Biopharmaceuticals, he said. "It's been a very well-validated target for the last few years, but there haven't been any good inhibitors that have come out yet," he said.

In exchange for several candidate PKB inhibitors, AstraZeneca will pay Astex $5 million up front, research funding, and milestone payments of as much as $270 million, "subject to the satisfactory achievement of development, regulatory, and sales targets," the companies said in a statement last week. Astex will supply the drug candidates to AstraZeneca over a period of 18 months. Astex is eligible to receive "up to double-digit royalties" on commercial sales of approved products, and it retains an option to co-promote any resulting products in the United States.

It may certainly be worthwhile for AstraZeneca to pursue PKB inhibitors as stand-alone agents, Stokoe said, "but obviously combination therapies may well be where your biggest bang for the buck is." He added that it is much simpler to get drugs approved as single agents than as combination therapies.

If PKB inhibitors work to improve the efficacy of EGFR inhibitors, clinicians will need to be able to identify tumors with activated PKB. "I think there would be tremendous drive for that, if there proves to be a body of data pre-clinically, and particularly clinically, suggesting attractive combinations selected on that basis," said Thompson.

But there are limitations to the current technology. "The problem with using [PKB activation] is, it's very non-quantitative, at least with the current methods," Stokoe, the UCSF researcher, said. Immunohistochemistry, even when it provides a yes-or-no answer, is still "somewhat suggestive," and qualitative rather than quantitative, he said.

In addition, there are other possible candidates — such as PI-3 kinase inhibitors, rapamycin and its analogs, and a drug called m-TOR — that may be effective in rescuing EGFR-inhibitor activity, according to Stokoe and his collaborator Daphne Haas-Kogan, whom Pharmacogenomics Reporter spoke to in June.

— Chris Womack ([email protected])

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