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Jeffrey Sosman, M.D., and colleagues are studying a new chemotherapy drug tailored for melanomas with a specific genetic alteration.



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“I feel very blessed; I’m very thankful,” Quigley says.

Puzanov presented initial findings from the Phase I trial at this year’s annual American Society of Clinical Oncology conference. Of 16 patients with BRAF-positive melanoma, more than half had their cancer shrink by at least 30 percent. Patients without the mutation had no response to the drug. The investigators have extended the Phase I trial to include additional patients, and they are preparing to launch Phase II studies, which will treat between 90 and 150 patients at 12 centers. Sosman is leading the Phase II trial.

“The world of melanoma treatment has changed,” Sosman says.

“It’s really very exciting to treat patients whose tumors have the right genetic profile with this drug and expect them to respond, and for the most part they do.”

The BRAF mutation targeted by the PLX drug also is present in other cancers, Sosman points out. It’s present in about 40
percent of thyroid cancers, 10 percent to 15 percent of colon cancers, and 3 percent to 6 percent of lung cancers. A trial under way in colon cancer patients with the mutation is showing response rates similar to the melanoma studies.

These findings highlight a shifting view of cancer – rather than being a disease known primarily by its tissue of origin (breast, colon, lung), it is moving to a disease classified by the genetic mutations that drive it. And this change has implications for
therapy, Sosman notes.

“Cancers of the same genetic abnormalities should be treated the same whether they come from the skin or the colon or the lung,” he says. “I think that’s a concept that is really going to change our approach to treatment.”

This is the crux of the personalized oncology initiative that Pao is leading at Vanderbilt-Ingram – to put into place the systems that will allow physicians to routinely measure a tumor’s genetic changes and fit therapies to them.

Stitching the pieces together
Implementing a new clinical strategy requires the cooperation of multiple parts of the clinical enterprise, Pao points out, which could be an onerous task. But at Vanderbilt-Ingram, which he joined this year, Pao has found a culture of collaboration and “an openness to new ideas and trying new things that might improve patient care.”

With the aid of Cindy Vnencak-Jones, Ph.D., and colleagues in the Department of Pathology’s Clinical Molecular Genetics
program, Pao is developing a platform to test for multiple genetic mutations at the same time.

The goal is to develop tests for between 30 and 50 mutations. Pao and colleagues are “mining” databases of reported mutations, in order to build melanoma- and lung cancer-specific panels. Tested mutations will have relevance with respect to existing or emerging targeted therapies. Later, they will develop panels to detect mutations specific to other cancer types.

The results of the tests will need to be integrated into the electronic medical record with algorithms that aid physicians in assigning therapies. Vanderbilt is a world leader in medical informatics, and Dan Masys, M.D., professor and chair of Biomedical Informatics at Vanderbilt, and his colleagues are working on the informatics needs.

“Many cancer centers are trying to move this kind of tumor genotyping and therapy planning forward, but the big question is how to do that in the most efficient manner,” Pao says. “I think that Vanderbilt has the right strengths to really make this happen.”

The initiative is being supported by the Robert J. Kleberg, Jr. and Helen C. Kleberg Foundation and an anonymous foundation. Foundation support is especially important, Pao says, because it is difficult to gain National Institutes of Health funding for “nuts and bolts” implementation efforts like this.

Ultimately, Pao thinks that using genetic measurements to guide therapy decisions will become routine, something that we won’t even call “personalized” anymore.

But he is quick to acknowledge that we’re not there yet.

We still need the results of ongoing efforts that are defining the genetic mutations in cancers – particularly those mutations to which tumors become “addicted,” Pao says. We need more and better drugs to hit those targets. We need to understand how tumors that initially respond to targeted medicines become resistant – something Pao and his colleagues have done for lung cancers that become resistant to Iressa or Tarceva – and use that information to identify new targets and new drugs.

Despite the hurdles, Pao is excited.

“The genetic alteration that causes CML – BCR-ABL – was discovered more than 30 years ago, but it wasn’t until the last decade that we had a drug that could be used in patients with that mutation,” he notes. In contrast, investigators identified a new genetic mutation (called EML4-ALK) in 5 percent of lung cancer patients just two years ago, and already a specific inhibitor has moved through Phase I trials with a 50 percent response rate in patients with the mutation.

“The pace of discovery is increasing and we’re going to be able in the next five to 10 years to routinely assign therapies based on the genetic makeup of patients’ tumors.”

Perfectly fitted therapies. My grandma would be pleased. bullet

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