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Combination targets: some drugs may work best when they work together
Date:10/24/2007

ided to look elsewhere along the MEK and PI3-kinase pathways, eventually trying MEK inhibitors in combination with a number of inhibitors along the PI3-kinase pathway, Dr. Korn said. The resulting studies show that, with the select combination of targets, we can elicit a synergistic effect between anti-cancer drugs that are much stronger than either drugs effect alone. Dr. Korn concludes the key to ultimate MEK inhibition may be to bypass the MEK pathway altogether. The researchers found that targeting PI3-kinase and a protein farther down the pathway, called TOR, caused apoptosis in the breast cancer cells. One molecule known to inhibit TOR is rapamycin, an immunosuppressant whose anti-cancer effects are under study. Dr. Korn and his colleagues are currently studying the combination in other breast cancer cell lines in anticipation of later clinical trials.

AZD6244 (ARRY-142886), a potent and highly selective MEK1/2 inhibitor, demonstrates anti-HIF properties, and increases the therapeutic response in a lung tumor xenograft model when combined with radiotherapy: Abstract A 244.

Researchers at the University of Manchester have found that a therapeutic currently in Phase II clinical trials is more effective at shrinking tumors when combined with radiotherapy. In a mouse model for human lung cancer, AZD6244 may increase the potency of radiotherapy by shutting down the cellular machinery that allows cancer cells to cope with a lack of oxygen, a state called hypoxia, they report.

AZD6244 is a small molecule inhibitor developed by AstraZeneca to bind to and inhibit MEK1 and MEK2 proteins, which together form a critical point on the pathway that controls the ongoing survival of cells. Defects along the pathway can lead to increased cell proliferation and cancer, and the drug was developed to halt this important route toward tumor progression. The MEK proteins are also part of the pathway that controls the production of HIF-1, the hypo
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Contact: Greg Lester
greg.lester@aacr.org
267-646-0554
American Association for Cancer Research
Source:Eurekalert

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