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Duke Team Identifies Phosphoprotein Signatures That Could Predict Breast Cancer Risk

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By Adam Bonislawski

Duke University researchers in collaboration with molecular diagnostics firm Theranostics Health have identified three phosphoprotein activation signatures in precancerous breast tissue that could potentially be used to identify women at high risk for developing breast cancer.

With these signatures, the researchers are launching trials to investigate the effectiveness of several breast cancer prevention agents and working to develop a prognostic for stratifying precancer patients according to their chances of progressing to actual breast cancer, Victoria Seewaldt, director of the prevention program at the Duke University Comprehensive Cancer Center, told ProteoMonitor.

"The Holy Grail here would be to be able to start saying, 'This is a bad precancer, this is a no-big-deal precancer,'" she said. "This is a tool that allows us to start saying, 'This person is going to get into trouble and this is why they're going to get into trouble.'"

Seewaldt presented the protein signature work this week at the Ninth Annual American Association for Cancer Research Frontiers in Cancer Prevention Research Conference in Philadelphia. The signatures — each of which comprise roughly 15 proteins in the Akt/mTOR/PI3K/cSrc, EGFR/MEK/ERK, and HER2/bcl-2 pathways — will also aid in research into the effectiveness of various preventive agents targeting breast cancer, allowing researchers to test potential agents to "make sure they're affecting the pathways that we think we should be targeting," Seewaldt said.

The Duke team is about to launch a 300-subject Cancer and Leukemia Group B trial that will re-examine the effectiveness of tamoxifen as a prevention agent as well as a 50-subject trial investigating the use of vitamin D in breast cancer prevention. Both trials will run twelve months, with fine-needle aspirate tissue samples taken at three points throughout.

The vitamin D trial is aimed at African-American women in particular, Seewaldt said, noting that one of the pathways her team is investigating seems "to link up very nicely with vitamin D," which, she said, African-American women often have in very low levels.

The researchers are also in negotiations to collaborate with an unnamed pharmaceutical company that produces a kinase inhibitor targeting one of the proteins implicated in their work.

In addition to collaborating with drugmakers on new agents for breast cancer treatment and prevention, Seewaldt also plans to look at off-target effects that already established drugs may have on proteins in the identified signatures, she said.

"One of the things you've got to be very careful about with prevention is that you have to minimize toxicity," she said. "So we want to work with drug companies looking for [new] kinase inhibitors, but we also want to look for drugs that have off-target effects that we can use really cheaply and that have a really long record of safety."

For example, tamoxifen has been used for roughly a decade as a preventive agent for breast cancer. However, because of its side effects, which include strokes and blood clotting, many at-risk women decline to take it.

"We need to find acceptable alternatives — things that work but also have acceptable toxicity — especially for younger women" Seewaldt said.

Statins and selective serotonin reuptake inhibitors like Paxil and Prozac are two classes of drugs the researchers are interested in for this purpose, Seewaldt said. Statins have shown promise in recent years as a preventive agent for a variety of cancers, while SSRIs have been shown to reduce the incidence of colon cancer. The team is currently negotiating with a pharma company to set up a study doing off-label testing for an unnamed SSRI. The study will last one year and include 50 precancerous subjects at high risk for ER-negative breast cancer.

The Duke scientists have been collaborating with Theranostics and the labs of the firm's co-founders, George Mason University researchers Lance Liotta and Emanuel Petricoin, on the reverse phase protein microarray work used to quantify the activation levels of the roughly 60 phosphoproteins the group is examining. Seewaldt's team has been taking patient samples and microdissecting them, then sending them to Theranostics and the Liotta and Petricoin labs to be run on the RPMA platform, she said.

The groups' collaboration began in 2008, and last year Duke was awarded a Promise Grant from the Susan G. Komen Foundation based in part on preliminary research stemming from their work together.

Seewaldt suggested that if further research confirms the protein signatures are in fact capable of reliably predicting precancerous patients' risk of progression to breast cancer, Theranostics could be a possible partner in bringing a test based on the work to market.

"That would be something we would be very interested in doing," she said. "You could have the signature and it could be run through Theranostics. We could partner with them."

John Hartwell, Theranostics' senior director of business development, told ProteoMonitor that it was too early for the company to comment on any potential tests based on Seewaldt's work, noting that signatures identified in the discovery phase "have to be validated. That's what [Seewaldt] is doing now."

Going forward, her team will prospectively follow roughly 750 subjects — 350 by taking fine-needle aspirate samples and 400 via MRI — to determine the signatures' prognostic capabilities.

"We have tools, but it would be overstating it to say that we know what will happen to these women," she said. "Adding the protein signatures is new, and we're going to have to see what happens. We're predicting this will be very helpful, but we can't say for sure until we watch the women."

According to Seewaldt, roughly 10 percent of precancerous women go on to develop breast cancer, although that number can be as high as 50 percent to 70 percent in certain high-risk populations.

"This would be a very useful tool — like an [OncotypeDX], but for precancer — to help us say, 'We've got to get on this and be aggressive,' or 'We can leave this alone and be less aggressive,'" she said.

The group is currently in the process of submitting two papers based on the protein signature work — one that has been accepted pending revision at Cancer Epidemiology, Biomarkers & Prevention, and another that will be submitted to a journal still to be determined.


Have topics you'd like to see covered in ProteoMonitor? Contact the editor at abonislawski [at] genomeweb [.] com.

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