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GMU Developing Proteomic Profile to Personalize Gleevec Treatment for CRC; Novartis Provides Funding

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By Turna Ray

George Mason University researchers are working with the cancer division at Inova Health System in Virginia to identify markers that may eventually lead to the first protein activation companion assay, allowing doctors to personalize the treatment of late-stage colorectal cancer patients with the oncologic Gleevec.

Based on the outcome of this and future studies, Gleevec manufacturer Novartis may be able to expand the indication of the drug -- currently approved for the treatment of gastrointestinal cancers and chronic myeloid leukemia -- for the treatment of colorectal cancer. Although Novartis provided an undisclosed amount of funding for the GMU study, the company said it was too early to divulge its commercial interests for Gleevec in colorectal cancer.

The three-year study being conducted by GMU will be led by Lance Liotta and Emanuel Petricoin, co-directors of the university's Center for Applied Proteomics and Molecular Medicine, and will enroll 50 metastatic colorectal cancer patients whose disease has spread to the liver. Liotta and Petricoin will work with oncologists at Inova Health System to treat these patients with Gleevec in addition to standard therapy.

Researchers will use a reverse-phase protein microarray technology developed by GMU scientists to analyze secondary tumors and identify a unique molecular profile linked to drug response.

Using the array, the GMU researchers hope to "measure all [FDA-approved targeted therapies] quantitatively, at once, from a tiny needle biopsy," Petricoin told Pharmacogenomics Reporter last week via e-mail.

The reverse-protein microarray technology is what makes the current PGx research with Gleevec possible, by allowing researchers to look directly at protein function and not just gene mutations.

"The problem was [that], before the reverse-phase array, it was technically impossible to measure the broad-scale protein activation portraits from a tiny biopsy specimen, which [is something that] you need to do for personalized therapy-based applications and trials," Petricoin said. "We see gene mutation analysis as the first step and functional protein pathway activation analysis as the next new frontier for personalized molecular medicine."

The strength of this trial rests on the understanding that any companion assay must detect alterations at the protein level to be able to gauge drug response, Petricoin explained.

Until now most cancer tumor profiling has focused on genomics, and this research represents the first time a direct proteomic approach is being used to map drug response networks, Petricoin said. Furthermore, he noted that if he and his colleagues are able to accomplish what they're aiming for in this study, it could lead to the development of the first ever protein activation companion assay.

If the trial is successful, it would "suggest the administration of CRC with a companion proteomic test," he said.

Furthermore, a potential proteomic test developed out of this research would be novel since it would be based on the metastatic tumor, not the primary tumor like most diagnostic cancer tests. "Indeed, our finding that the Gleevec drug targets are activated was found only by looking at the metastatic lesion," Petricoin added. "We would have missed it if we only looked at the primary tumor."

The researchers are planning to report results from the first phase of the study approximately three months after finishing patient recruitment. Eventually, incremental and final study results will be presented at international meetings and in peer-reviewed journals.

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The current investigation is part of a larger ongoing effort by CAPMM researchers to tailor cancer patients' treatment with a single agent based on information provided by genomic and proteomic profiling.

"We want to test the concept that any targeted inhibitor, regardless of the organ site it has been approved for, will work in a much, much larger population of patients when one thinks in the aggregate," Petricoin said. "For example, the population of patients with metastatic colorectal cancer is much larger than GIST and CML; if you added up all metastatic disease, it's huge."

Gleevec for CRC?

Petricoin was tight-lipped about Novartis' potential interests in GMU's personalized medicine research efforts with Gleevec. However, he noted that Novartis and CAPMM are working together on various PGx research efforts.

"I can tell you that in talks with them, [Novartis], like other pharma, now realize the huge untapped potential of using existing US Food and Drug Administration-approved compounds for new indications," Petricoin said. He added that CAPMM researchers are also in discussions with Novartis about research involving other targeted therapies.

Certainly, Novartis has showed an interest in developing drug/diagnostic combination products to personalize treatments. Last January, Novartis launched an internal molecular diagnostics unit, hoping to spur Rx/Dx co-development products by matching genetic tests with therapeutics in the early stages of clinical trials.

The global firm is also attempting to launch in markets outside the US its painkiller Prexige with a companion diagnostic. The drug that was denied marketing approval by the FDA due to hepatic adverse effects and Novartis has said it has no plans to relaunch the drug in the US [see PGx Reporter 08-12-2009].

"One of the tremendous promises of personalized therapy is to use existing therapies in new ways -- for new indications," Petricoin said. "A vision that we have been proposing is a reorientation of thinking about therapy given by site (e.g., Gleevec only to patients with stromal tumors or patients with CML) to therapy given based on the underpinning functional derangement, which we think can occur across many cell types."

Using the reverse-phase protein microarray, the GMU researchers are hoping to run similar personalized drug response studies in various targeted oncologics, such as EGFR inhibitors, mTOR inhibitors, VEGFR inhibitors.

The array technology is proprietary to Theranostics Health, a GMU spinout founded by Petricoin and Liotta. The two researchers are also studying biomarkers related to cancer, heart disease, liver disease and obesity.

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