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Barrett's Esophagus MDx Test From Case Western Team Gets NCI Funding


NEW YORK (GenomeWeb) – Researchers at Case Western Reserve University and Medical Center recently won funding to develop a methylation-based biomarker test for Barrett's esophagus, the only condition known to predispose a person to esophageal adenocarcinoma.

The team is also developing a novel balloon device to obtain samples from the lower esophagus, potentially eliminating the need for endoscopy and biopsy, and making the test useful for low-cost screening.

The four-year grant was awarded late last month by the National Cancer Institute. It totals about $850,000 and was part of a request for applications specifically to fund assay validation of high-quality markers that could result in NCI-supported clinical trials.

The principal investigator on the grant, Joseph Willis, is a professor and vice chairman of pathology at Case Medical Center and CWRU and is part of the Barrett's Esophagus Translational Research Network (BETRNet) there.

Although the parameters of the test are still under development, the team has already applied to NCI to run two clinical trials in the Cleveland area, Willis told GenomeWeb in an interview.

The trials will evaluate the biomarker test — an assay of aberrant methylation of the gene for vimentin — on clinical specimens, but will also assess the novel collection device. "We'll have corresponding biopsies and be able to see whether or not the assay was as sensitive and specific as we think it will be," Willis explained.

The CWRU group will pursue test development with both PCR and next-generation sequencing, Willis said, since there are benefits to both types of assay. An NGS assay may lend itself to interrogating large numbers of samples simultaneously in a reference lab, while PCR can be done for a relatively reasonable cost, he said.

Besides developing the methylation assay and the collection device, the grant is also a "unique mechanism," according to Willis, with the lab and clinical validations going hand in hand. While the first part of assay development will involve determining the lab characteristics of the assay, the NCI grant ultimately also provides funding to take the test into the clinical arena.

Esophageal adenocarcinoma is increasing in incidence in the Western world, most commonly among middle-aged white males. Barrett's Esophagus is a precursor lesion to that cancer. It's essentially a change in the epithelium of the distal esophagus, "from squamous epithelium, like skin, to more of a glandular mucus producing [tissue]," Willis said, a condition that is thought to be a reaction to acid reflux.

Unfortunately, esophageal adenocarcinoma is one of the most lethal cancers, with 80 percent of patients dying of their disease, most within two years of diagnosis. Screening for the only known precursor lesion could be massively beneficial, but "it's very difficult to screen everybody with reflux by endoscopy and biopsy, because it is just too costly," Willis said.

The novel collection device could certainly lower costs. It is basically a textured balloon. A patient would swallow it, then the clinician could inflate it with air from a syringe when it reached the stomach. It could then be pulled and used to slough cells from the distal esophagus, deflated, and removed to collect cells for testing. A prototype has been tested and yielded 10 times the DNA needed for the proposed molecular assays, according to the grant abstract. 

"We've spent quite a bit of time engineering the surface of the balloon to maximize the amount of collection of material but yet still be able to collapse the balloon and pull it out deflated, so it is much more comfortable for a patient," Willis said, adding that an article describing preliminary studies of the collection device is currently under review.

Willis and his colleagues initially discovered that aberrantly methylated vimentin in stool was a biomarker of colon cancer. They later showed it was also characteristic of upper gastrointestinal pathologies and may be important in Barrett's Esophagus' progression to cancer, although the detection of the biomarker in the earliest stages of that premalignant precursor lesion was unexpected, Willis said. However, "When we found that, we said we can use this as a screening tool," he said.

In the colon, vimentin methylation could be related to the dysplastic process of epithelial-mesenchymal transition, but in Barrett's Esophagus that same process does not occur. So, at this point the mechanism is unclear, and the group is still investigating why the same marker would also be detected in metaplasia in the esophagus. "It's really quite interesting, but so far it is unknown," Willis said.

The group ultimately intends to develop the test into a US Food and Drug Administration-approved assay. Whether CWRU will license the test to reach this goal, or whether the group will collaborate with industry in some other way, is an area of active investigation and has not yet been determined, Willis said.