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Targeting the BMP4/pSMAD/CDX-2 axis for Eradicating Barrett’s esophagus

Final Report Summary - TARGETS4BARRETT (Targeting the BMP4/pSMAD/CDX-2 axis for Eradicating Barrett’s esophagus)

The goal of this project was to develop a cure for Barrett’s esophagus (BE) patients, a pre-malignant condition that predisposes patients to a highly malignant cancer named esophageal adenocarcinoma or EAC. As discovered in our lab, the distal esophagus of BE patients resembles the intestine due to the abnormal activation of the intestinal pathway named BMP4. Therefore, our hypothesis was that inhibition of this BMP4 pathway would block BE and control the appearance of the highly malignant EAC. We therefore generated llama-derived antibodies (VHHs) against BMP4. We found that these antibodies are more effective and specific than current BMP4 inhibitors and/or monoclonal antibodies. These findings might result from the fact that these VHHs target a small region within the BMP4-BMPR binding area which is highly important for functionality. Humanization of these VHHs into forms that are more apt for clinical introduction in patients were also generated and found to be as effective as the original VHHs. Next, we developed novel BE mouse models in which to test these VHHs. In short, we found that the anti-BMP4 VHHs generated in this grant not only were able to block development of BE but also can be used to treat EAC. These findings suggest that these anti-BMP4 VHHs might be highly suitable for treatment of Barrett’s esophagus as well as BMP4+ EAC tumors.