|
发表于 2011-3-17 22:32:50
|
显示全部楼层
来自: 中国广东深圳
*crizotinib, an inhibitor of the Met oncogene, also has anti-ALK activity.
*2 professors working in other ALK experiment.
William Pao, M.D., Ph.D., assistant director of personalized medicine at the Vanderbilt – Ingram Cancer Center in Nashville
Ross Camidge, M.D., Ph.D., a medical oncologist at the University of Colorado in Denver.
*Drug Company Clinical stage
PF-2341066 Pfizer Phase III and II for NSCLC;
GSK2141795 GlaxoSmithKline Phase I, solid tumors or lymphomas
CEP-28122 Cephalon Preclinical; IND expected 2010
AP-26113 Ariad Pharmaceuticals Preclinical; IND expected 2011 -- Earlier this year at the American Association for Cancer Research annual meeting, it was reported that AP26113 overcomes mutations in EML4-ALK that confer resistance to crizotinib (abstract LB-298).
Xcovery X-276 Preclinical
*As Pfizer’s inadvertent ALK inhibitor moves through phase III, competition is emerging. New compounds may avoid or overcome the drug resistance that is causing Pfizer’s patients to eventually relapse. A compound from Ariad Pharmaceuticals, for example, has shown 10-fold greater potency and specificity for ALK in cell lines than the Pfizer compound. Potency should, in theory, overcome resistance because a single mutation is less likely to block the drug’s effects. “With a very potent compound, then it’s much harder for [ALK] to wriggle out of inhibition by mutating itself,” said Ariad chief scientific officer Tim Clackson, Ph.D., “as opposed to a rather modestly effective compound, where one mutation can blow away the benefit.”
Preclinical studies support this idea. In cell line experiments reported at the 2010 annual meeting of the American Association for Cancer Research, Ariad scientists identified six different ALK mutations that conferred resistance to crizotinib. In mousemodels, crizotinib had no effect on these mutation-bearing xenografts, whereas the Ariad compound shrank the tumors.
The biotech company Cephalon is also targeting ALK drug resistance. In preclinical models, its lead compound avoids multidrug resistance (the cell’s ability to pump out the drug) that hinders crizotinib in these models, said Cephalon chief scientific officer Jeffry Vaught, Ph.D. Cephalon used its compound in cell lines to identify a “gatekeeper mutation” — the same mutation in the active site of ALK that causes drug resistance in other kinases. The company’s second-generation compound will target such resistant tumor clones, if they exist in humans. Cephalon plans to test the first compound by early next year in lung cancer patients who can’t tolerate crizotinib. Several other companies are also targeting ALK .But whether ALK is the beginning or the end of a trend is not yet clear. Despite the EGFR, KRAS, and ALK success stories in lung cancer, widespread personalized therapy still seems a long way off. Mutation combinations for any given tumor type vary widely by individual, and which are drivers and which are passengers is not always apparent. |
|