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Labeled peptide bound the claudin-1 target in colorectal cancer models

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Affinity probes show promise for enhancing lesion detection

The application of fluorescent affinity probes described in this study is groundbreaking. In the context of advanced imaging techniques, including chromoendoscopy, narrowband imaging, high magnification, and confocal endomicroscopy, this study describes a specific molecular probe. That is a major advance in the area of personalized medicine.

While most would agree that detection of polypoid adenomas does not generally require advanced imaging technologies, the genetically engineered mouse model used in this study is useful for proof of concept. It is, however, important to note that lesions were not detected from a broad area; polyps were labeled during a 5-minute incubation with the fluorescent-tagged peptide and the area was then washed. While the fluorescent intensity of lesions relative to surrounding nondysplastic mucosae were impressively elevated in both polypoid and flat adenomas relative, it is important to note that there was significant overlap between normal mucosae, hyperplastic polyps, sessile serrated adenomas/polyps, and traditional adenomas. While the limited sensitivity and specificity make it unlikely that the probe used here, which targets a surface protein that is only modestly upregulated in dysplasia, will be of great value. However, the idea of specifically detecting lesions using affinity probes does have promise.

On the basis of this study, some might ask whether biopsy and histopathologic examination can be replaced by intravital affinity labeling. At this point, the answer must be no, as the sensitivity and specificity of labeling techniques are far below that of traditional histopathologic examination, even for straightforward lesions such as those studied here. Yet as a means to enhance the sensitivity of sampling when surveying large areas, such as Barrett’s esophagus or long-standing ulcerative colitis, the approaches described in this study point the way to a bright future.

Jerrold R. Turner, M.D., Ph.D., AGAF, is in the departments of pathology and medicine (GI), Brigham and Women’s Hospital, Harvard Medical School, Boston.


 

FROM CELLULAR AND MOLECULAR GASTROENTEROLOGY AND HEPATOLOGY

References

An optically labeled peptide rapidly and specifically bound the claudin-1 membrane protein, a “promising” target for early detection of human colonic adenomas, according to a study published online in the March issue of Cellular and Molecular Gastroenterology and Hepatology.

If the peptide holds up in human studies, it might one day be used to screen high-risk patients with multiple polyps, inflammatory bowel disease, Lynch syndrome, or a family history of CRC, said Dr. Emily Rabinsky and her associates at the University of Michigan in Ann Arbor. Peptides can be delivered topically to mucosa in high concentrations to maximize binding and image contrast while minimizing the risk of systemic absorption and toxicity, they added.

Adenomatous polyps express early molecular targets that are candidates for enhanced CRC surveillance. This research area is important because more than 35% of premalignant colonic lesions are flat and therefore difficult to visualize. As a result, up to 25% of adenomas are missed during typical white light colonoscopy. Furthermore, premalignant adenomas cannot be distinguished grossly from noncancerous hyperplastic polyps, the researchers noted (Cell Mol Gastroenterol Hepatol. 2016 [doi: 10.1016/j.jcmgh.2015.12.001]). Claudin-1 is an integral membrane protein that is known to be overexpressed in human colorectal and squamous cell neoplasias as well as in cancers of the human pancreas, thyroid, cervix, stomach, and nasopharynx. For the study, the investigators used gene expression data to confirm that claudin-1 is an early target in colonic adenomas, and then performed phage display against the extracellular loop of claudin-1 to identify the claudin-1-specific RTSPSSR peptide. After labeling the peptide with Cy5.5, they characterized its binding parameters and confirmed that it also specifically binds to human CRC cells. Next, they performed in vivo fluorescent colonic endoscopy of CPC;Apc mice, which spontaneously develop colonic adenomas. They also used immunofluorescence to confirm that RTSPSSR binds specifically to adenomas from the proximal human colon.

Claudin-1 expression was 2.5 times greater in human colonic adenomas compared with normal colonic mucosa, the researchers found. Furthermore, the RTSPSSR peptide specifically bound claudin-1 in knockdown and competition studies. Binding to CRC cells occurred in 1.2 minutes, with an “adequate” affinity of 42 nmol per liter, the researchers said. Moreover, the peptide specifically bound to both flat and polyploid murine colonic adenomas, with a significantly higher target-to-background ratio compared with normal in vivo images. In addition, immunofluorescence was significantly more intense for peptide that bound to adenomas and sessile serrated adenomas from the proximal human colon compared with normal tissue and hyperplastic polyps.

“Future development of this peptide will require in vivo clinical validation in human studies,” said the investigators. “Although we found promising results with this peptide alone, disease heterogeneity in a broad patient population may require use of additional targets using multiplexed imaging methods.” Nonetheless, this peptide can help detect multiple targets with a single topical application and at relatively low expression levels, they noted.

The study was partially funded by the National Institutes of Health and by Mary L. Petrovich. Dr. Rabinsky and two coinvestigators are co-inventors on a provisional patent on the claudin-1 peptide. The other researchers had no disclosures.

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