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MSKCC Scientists Develop First Controllable EGFR-Mutant Mouse for Iressa, Tarceva Study

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There is now a mouse strain engineered to help researchers study the epidermal growth factor receptor function, EGFR drug response, and certain lung adenocarcinomas.

The mice, developed by researchers at the Memorial Sloan Kettering Cancer Center in New York, harbor a promoter sequence that can be used to turn mutated EGFR genes constitutively on and off in the mice at will. When in the "on" position, the EGFR genes cause lung cancer, "and when you turn the gene 'off,' the tumors go away," said William Pao, an MSKCC researcher who co-authored the study, in an interview last week with Pharmacogenomics Reporter.

The investigators feed the mice doxycycline to activate mutant EGFR, Pao said.

"This tells you that the lone tumors that develop are dependent on the presence of that mutant protein for survival," said Pao.

The investigators' findings can be found in the June 1 issue of Genes and Development.

Interestingly, giving the mice Tarceva has a similar effect to turning the gene off completely. "The mice can help us study not only the initiation, progression, and maintenance roles of these mutant EGFRs in lung cancers, but then we can also use them to test various therapies to try to develop more effective ways of giving them Tarceva, or to test other EGFR inhibitors or other drugs that might play a role in the same pathway that could be affected," Pao said.

Another use the mice can serve in lung cancer research involves acquired resistance to Tarceva, in which tumors disappear but eventually come back. The researchers plan to investigate what genetic or other changes allow tumors to recur in order to develop strategies to suppress that resistance.

About 10 percent of non-small cell lung cancer patients in the United States and about 25 percent of East Asian non-small cell lung cancer patients carry similar EGFR kinase-domain mutations. The mutations render these patients more susceptible to Iressa and Tarceva.

In a typical experiment, researchers examine the mice using magnetic resonance imaging after giving them tumors to track their response to anti-cancer drugs. "Unlike a human, you can sacrifice the animal and you can look at how much tumor is left in the tissue," allowing more detailed studies, said Pao. The model also allows researchers to examine protein activation cascades to identify new drug targets, he said.

Dupont holds a patent that covers the use of cancer-prone transgenic animals in drug testing, so companies who would like to use the MSKCC mouse model must pay Dupont royalties. However, the mice will be available for licensing from the MSKCC group, depending on the exact terms of the patent.

While academic researchers are exempt from paying Dupont royalties, Pao said that the licensing requirement can be "prohibitive" for commercial users. "You'd think there would be a lot more mouse models that would be used for testing like this, but they're not used a lot because of the expense," he said.

— Chris Womack ([email protected])

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