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Liotta, Petricoin Using Protein Array Technology to Test Gleevec for Colorectal Cancer

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By Tony Fong

Lance Liotta and Emanuel Petricoin have launched a clinical trial using technology they developed to test whether the cancer drug Gleevec can be used to treat colorectal cancer, in what they said it is one of the first applications of proteomics technology for personalized medicine.

Announced last week, the trial, which began in the summer, specifically targets the efficacy of Gleevec as a treatment for metastatic colorectal cancer. Gleevec, manufactured by Novartis, was approved by the US Food and Drug Administration in 2001 for the treatment of chronic myelogenous leukemia and is also used for gastrointestinal stromal tumors.

Along with Petricoin and Liotta, who are co-directors of George Mason University's Center for Applied Proteomics and Molecular Medicine, co-principal investigators of the trial includes Kirstin Edmiston, medical director of cancer services at Virginia's Inova Health System; and Alexander Spira, director of the Fairfax Northern Virginia Hematology Oncology Research Program.

Novartis is funding the three-year trial, which will include up to 50 men and women with late-stage colorectal cancer that has spread to the liver. To date, about four patients have been recruited for the trial.

Liotta and Petricoin will use a protein microarray technology they developed and commercialized in 2006 to sample metastatic lesions and create a proteomic profile to show which protein pathways or drug targets are activated in the lesion. From this, they expect to be able to determine if Gleevec can be used to effectively treat an individual with the disease.

"This is one of the first examples … where a protein array technology is mature enough to get to the bedside where the data coming out of the array is actually used to stratify patients, to decide which patient is getting Gleevec," Petricoin told ProteoMonitor this week. "So it's not an observational trial."

The technology is based on a reverse-phase protein microarray developed by Liotta and Petricoin that allows researchers to look at the activity level of proteins in tissue specimens, which in turn allows them to measure the activity of protein drug targets in a patient's biopsy in response to specific drug therapies [See PM 03/29/07].

Based on those results, an individual course of treatment can then be developed for the patient.

According to Petricoin, the discovery that Gleevec may be useful in treating metastatic colorectal cancer was an unexpected one. Using their technology to analyze tissue from primary tumors and metastatic lesions from the same patients with colorectal cancer, the GMU team noticed that there were "big differences in the signaling activation in the metastases compared to the primary" tumor, Petricoin said.

The importance here is that in most cases, treatment of the metastatic lesion has been based on a molecular portrait of the primary tumor, which as it turns out can be different from that of metastasis.

"If the metastasis is different from the primary, that would be very important to know," he added, because patients with colorectal cancer more often die from liver, lung, or brain metastases and not from the primary tumor.

Further, when they looked at the metastatic tumors, they found higher levels of phosphorylation in the drug targets of Gleevec — abl, C-kit, and PDGF — compared to the phosphorylation levels in those proteins in primary tumors.

The GMU researchers went into their experiments with the hypothesis that the signaling networks in the metastatic lesions would be different than in the primary tumors "because it's a different micro-environment," but they weren't sure of what they would see, Petricoin said.

But because their technology could measure "many, many, many" signaling molecules simultaneously from a small needle biopsy, he and his collaborators were able to take a shotgun approach in comparing the signaling activation between metastatic and primary tumors.

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The researchers observed other signaling pathways that were activated and which may be considered for future clinical trials, but "the beauty here was that every single one of the Gleevec drug targets was elevated … in the metastasis."

Based on their finding, they went to Novartis, which agreed to fund the clinical trial.

Petricoin and Liotta said they did not know the cost of the trial. Novartis declined to be interviewed for this story, but in a statement to ProteoMonitor said that it "continues to explore Gleevec in a number of disease areas. As far as next steps in the Liotta/Petricoin trial, future plans will be determined based on the results of the trial."

Petricoin said that Novartis will not be involved in any of the scientific work in order to avoid any appearance of a conflict of interest.

New Indication for Gleevec?

The potential ramifications of GMU's findings for Novartis are clear. Gleevec generates close to $4 billion in revenues, and colorectal cancer, the third-most commonly diagnosed cancer in the US, could represent another revenue channel for the drug firm.

According to the National Cancer Institute, about 147,000 new cases of colorectal cancer were diagnosed in the US last year. Nearly 50,000 Americans died of the disease in 2009. The figures include both colon and rectal cancer.

The trial underway is designed to test what effect Gleevec in combination with other therapies has on metastatic tumors. Patients for the trial are those for whom first- and second-line therapies have already failed, resulting in recurrence of the cancer.

A liver biopsy will be taken of each patient from which a molecular profile of the metastasis will be created. The biopsy will then be analyzed by Liotta and Petricoin's reverse phase protein microarray technology, and a physician report will then be generated on the level of activation of the Gleevec drug targets. If the patient has a high score, he or she will be administered Gleevec for 28 days by itself.

Another liver biopsy of the patient will then be performed to see whether the drug has hit the drug targets. The patient then will be started on EGFR therapy, a standard of care for colorectal cancer. Then Gleevec is given to the patient along with EGFR, and the metastasis is monitored radiologically to see whether there is shrinkage.

The biopsy material will also be analyzed to determine any correlation between [the activation of drug targets and response. All the steps will be carried out in 72 hours.

Although preliminary research has observed elevations in Gleevec's drug pathway, what remains to be answered is whether those elevations are driving the tumor's growth or if they are just a secondary event, or whether the tumor "can just immediately rewire around having this pathway turned off," Petricoin said. "What we are hoping is that by going in with techniques like the array [and] being able to map the circuitry of the cell, that that is information we can use to decide" what therapies to use.

If the results from the trial indicate that Gleevec has, in fact, some utility against metastatic colorectal cancer, the next step would be conduct larger multi-center studies.

In addition to testing Gleevec for colorectal cancer, in about a month, the GMU research team will begin another trial targeting breast cancer. Again using their reverse-phase protein microarray, the researchers will test the effects of every FDA-approved targeted therapy for cancer — 13 in all — including Avastin, EGFR, AKG, mTOR, and Gleevec.

"We hope to be able to provide information to physicians about which targets are activated" so that they can choose the most appropriate one for each patient, Petricoin said.

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The Side-out Foundation, which supports research and other efforts against breast cancer, is funding that effort.

Liotta and Petricoin created a company Theranostics Health in 2006 to commercialize their reverse-phase protein microarray technology, though it is not involved in the clinical trial.

Since the technology was first launched and made available as a service, its capabilities have been built out so that it is now a calibrated assay.

"When we say that a sample has a high Gleevec drug target score, [high] compared to what? When we say high, how do we know it's high?" Petricoin said. "We have a whole series of calibrators and controls that we've developed, that we print on every array, so that we know beforehand what really is high and low."

They have amassed "a wealth" of population data from tumors and metastases that can be used as a baseline comparison for studies such as the colorectal cancer clinical trial. They have also developed analytical techniques on the arrays such as ways to do background subtractions and protein optimization. And, said Liotta, they now have doubled the number of anti-phospho proteins and "important analytes in different signaling networks of cells."

Because the colorectal cancer clinical trial is the first time that the reverse-phase protein microarrays are being tested in a clinical setting, he and Petricoin said that it marks an important transition for the technology.

"We have many clinical trials in the queue where we have been able to demonstrate technical competency — that we can bring in tissue [and that] we can in a very short number of days laser capture microdissect and analyze material on the arrays" Petricoin said. "And the arrays have attained an analytical precision and accuracy now in our laboratory that we can start to generate information to actually treat patients."

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