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Cedars-Sinai Medical Center Scientists Find Another Possible Iressa Non-Response Marker

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There is a new potential marker of tumor non-response to Iressa on the scene.

Researchers at Cedars-Sinai Medical Center write in this week's online issue of the Proceedings of the National Academy of Sciences that the protein EMP-1 is present in the cellular membranes of patients whose tumors do not respond to the AstraZeneca drug.

The development "may enable us to identity patients who won't respond to the drug," said David Agus, senior author of the study and Research Director at the Louis Warschaw Prostate Cancer Center at Cedars-Sinai, in a statement this week. "If we know who won't respond, we can explore other treatment options sooner and use [Iressa] when patients will benefit," he said.

In the absence of methods to identify responders and non-responders, approximately 11 percent of non-small cell lung cancer patients respond to Iressa. The FDA took the second-line drug off of the market after December clinical trial results showed a lack of increased survival in a broad population. Currently, doctors can prescribe the drug to their patients only if they have responded to it already.

Along with other putative biomarkers, such as KRAS, activated PKB/AKT, and certain EGFR mutations, the protein EMP-1 may take a place as a panel of tests predictive of response or non-response to some EGFR inhibitors, a therapeutic category that includes the drugs Iressa, Tarceva, and Erbitux, which are made by AstraZeneca; Roche Pharmaceuticals, Genentech, and OSI Pharmaceuticals; and ImClone; respectively. But like certain EGFR mutations, evidence for EMP-1's diagnostic ability is based on a small study and it runs the risk of being brought into question by alarger effort.

The investigators examined the tumors of 39 patients who were being treated with Iressa during a clinical trial of the drug in non-small cell lung cancer. Of the 14 patients whose tumors stopped responding to Iressa, all expressed EMP-1, as detected by immunohistochemistry. None of the patients who responded to the drug expressed EMP-1.

The marker is not perfect, of course. One patient who did not initially express test positive for EMP-1 was later tested positive after acquiring resistance to Iressa. "This tells us that the absence of EMP-1 does not completely predict whether a person won't stop responding to [Iressa]," said Angali Jain, a Cedars-Sinai researcher and the PNAS paper's first author.

EMP-1 expression and acquisition of gefitinib clinical resistance was independent of gefitinib-sensitizing EGFR somatic mutations, the authors said.

The results suggest EMP-1 engages in cross-talk with the EGFR signaling pathway, the authors added.

In the process of discovering EMP-1, the researchers treated mice having androgen-independent prostate-derived tumors with Iressa, and transplanted tumor cells to new mice until they had created new tumors that failed to respond to the drug.

Interestingly, the Cedars-Sinai scientists found that EMP-1 expression was common to two tumor types that do not respond to Iressa treatment, squamous cell carcinomas and adenocarcinomas.

Cedars-Sinai did not respond to telephone calls before deadline. It remains unclear whether the researchers have been approached by diagnostics or pharmaceutical companies about the possibility of developing the diagnostic capability of EMP-1.

— Chris Womack ([email protected])

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