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A strategy for targeting a mean mutation

Suresh Ramalingam, chief of thoracic oncology and director of medical oncology, Winship Cancer Institute

The "divide and conquer" approach to cancer therapy has been increasingly prominent in recent years. This strategy identifies drugs that are particularly effective against tumors carrying certain growth-driving mutations.

Two recent examples include crizotinib, approved by the FDA for non-small-lung cancer with a translocation in the ALK gene, and vemurafenib, approved for melanomas with mutations in the B-raf gene.

One inevitable drawback: if someone's tumor doesn't carry the specified mutation, these drugs can't help. The mutation that makes a tumor vulnerable to crizotinib is found in only a small percentage of lung cancers.

So when designing a research program in lung cancer, why not go after the targets that cause the most disease?

That's the rationale behind Winship researchers' hunt for ways to attack the worst of the worst: lung cancers with mutations in K-Ras, a gene that has long been considered "undruggable."

Lung cancers with mutations in K-Ras, which make up around a quarter of all non-small cell lung cancers (NSCLC), are known to be resistant to both chemotherapy and newer drugs. In the 1980s, the K-Ras gene was one of the first oncogenes identified, by virtue of its presence in a virus that causes cancer in rats. Basic scientists have examined ways to inhibit the effects of mutated K-Ras in cancer cells, without much success.

Suresh Ramalingam, Winship's chief of thoracic oncology and director of medical oncology, says K-Ras and another frequently mutated gene in lung cancer, LKB-1, are at the center of Winship's strategy for lung cancer research. That strategy has been identified as a major focus for the Emory Lung Cancer NCI- funded program project grant entitled "Targeting Cell Signaling in Lung Cancer to Enhance Therapeutic Efficacy." Winship's deputy director, Fadlo R. Khuri, and Haian Fu, both of whom have devoted a number of years to identifying cancers with K-Ras mutations, lead that application, and targeting K-Ras is a major focus of a project in the grant co-led by Ramalingam and Yuhong Du.

"The significance of K-Ras mutations, as far as poor outcomes with chemotherapy with NSCLC, has been well known, " Ramalingam says. "The field has been looking for a way to target K-Ras for a long time. You can think of this as a big white elephant sitting in the room, demanding attention."

Now research led by Winship researchers has provided leads for two strategies that may help doctors capture this elusive target. Both involve anticancer agents that are already in clinical trials.

Full Story in Winship Magazine »

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