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USC, U of Miami Researchers Develop Nine-Protein Panel for Predicting Bladder Cancer Progression


A team led by researchers at the University of Southern California and University of Miami has developed a nine-protein panel for predicting the progression of bladder cancer.

In a recently published study of primary tumors from 212 bladder cancer patients, the panel, combined with patient smoking history, improved predictions of survival compared to standard clinicopathological data alone.

The team has since begun additional retrospective and prospective studies of the panel in hopes of validating it and moving it into clinical practice as a tool to guide treatment in both neoadjuvant and adjuvant settings, Anirban Mitra, a USC researcher and author on the study, told ProteoMonitor.

The panel consists of the proteins Bax, caspase-3, apoptotic protease-activating factor 1, Bcl-2, p53, p21, cyclo-oxygenase-2, VEGF, and E-cadherin, which were selected, Mitra said, to cover a wide variety of pathways associated with the disease.

"We proceeded under the hypothesis that for cancer in general and for bladder cancer in particular, it's not just an alteration in one particular marker or pathway, but the combination of several different pathways," that would prove the best prognostic for the disease, he said.

"So when we selected these markers… we wanted to combine a multitude of commonly implicated pathways that you would think would be associated with cancer progression," he added. "These were the most representative markers for those pathways."

Ultimately, Mitra said, the researchers aimed to test the idea that, more than changes in specific markers, prognosis was linked to the overall number of markers dysregulated in a given tumor – a notion, he added, that their findings bore out.

In the study, published this week in the journal Cancer, patients were assigned to one of three groups: one in which three or fewer markers were altered; one in which four to six markers were altered; and one in which seven to nine markers were altered. In subset analyses of these categories, the authors found that increasing numbers of protein alterations were associated with increasingly poor patient outcomes.

"It's the combination of markers, and, more importantly, the number of marker alterations associated with cancer progression," Mitra said. "The more [protein] alterations that a primary tumor has in terms of just pure frequency, it becomes a worse prognosis, irrespective of which markers you are specifically looking at."

Indeed, while the researchers found that only E-cahedrin, p53, and Apaf-1 had value for predicting outcome alone, the addition of the panel plus smoking history to the standard clinicopathological data raised the prognostic accuracy as measured by area under the receiver operating curve from 75.6 percent to 85.4 percent.

The researchers used immunohistochemistry to profile the markers in the patient samples, a technique that, Mitra noted, has the advantage of being relatively easy to adopt in the clinic. This, he said, was one reason the researchers looked to a proteomic rather than genomic approach when putting together the panel.

"When you look at direct clinical applicability, a procedure like immunohistochemistry is widely available at pretty much most CLIA-certified labs," he said. This is not the case with "something like microarray testing, which is probably only available at select tertiary referral centers."

Additionally, Mitra said, the researchers needed a sample set with long patient follow-up, which led them toward formalin-fixed paraffin-embedded tissue – a format to which immunohistochemistry is perhaps more amenable than many forms of genomic analysis.

The study looked at 212 primary urothelial carcinoma of the bladder tumor samples obtained through the Los Angeles County Cancer Surveillance Program. The samples included both non-muscle invasive tumor patients treated by transurethral resection and muscle invasive tumors that required radical cystectomy, suggesting, Mitra said, that the marker panel could prove applicable to both forms.

While some protein and genetic markers are currently in use to diagnose and predict progression of bladder cancer, the disease lags behind other cancers like breast and colon in terms of applying molecular information to treatment, Mitra said.

"Most of the [bladder cancer] patient management today is primarily based on pathological staging, the tumor stage when the patient has surgery," he said.

He added that certain centers, including USC, are using smaller numbers of markers such as p53 to guide therapy, but that "a comprehensive integration of markers into clinical practice is not routine as of yet."

Predictive Biosciences is one firm trying to bring molecular markers to bladder cancer treatment. The company's CertNDx test, which it offers out of its Cleveland-based CLIA certified lab, analyzes mutations to the FGFR3 gene, methylation status of NID2 and TWIST1, and the presence of the MMP-2 protein to detect the presence of bladder cancer.

The company has marketed the test largely as a diagnostic, but it also has applications for molecular grading that can aid in guiding treatment, similar to the USC panel.

Since completing the study detailed in the Cancer paper, Mitra and colleagues have launched additional retrospective studies, collecting three new cohorts of between 300 and 500 patients. They are also planning to launch two prospective studies, including one at USC, to further test the markers.

The panel "needs a little bit more validation before it is directly applied to decision making," Mitra said, but, he added, initial data from the recently launched retrospective studies "looks pretty promising."

The researchers have no plans to patent the test, he said, explaining that many of the markers have already been used individually for related purposes, "so there is a lot of prior art already."

Not pursuing a patent also ensures that in the case the test does prove effective, "academics and everyone can have the flexibility to use it without issues of IP in the way," Mitra said.