Novel targets for prevention and inhibition of proliferation and metastasis of esophageal adenocarcinoma

Esophageal adenocarcinoma (EAC) is a highly malignant disease with a dismal prognosis. In the Western world, EAC presents a growing number of new cases, which poses a health challenge in recent years. Novel molecular treatments to improve patients’ outcomes are an unmet medical need. Barrett’s esophagus (BE) is a metaplastic condition that predisposes for EAC. Non-dysplastic BE (NDBE) accounts for a large proportion of the BE population and carries a relatively low risk for developing EAC. The challenge for NDBE is the difficulty to estimate its malignant progression risk. This often leads to overtreatment and frequent endoscopic examinations, thereby generating a healthcare burden. In this thesis, BE patients and EAC patients’ specimens were used for RNA sequencing, gene expression, gene variation and protein expression analyses. This thesis found that upregulation of the PXR signaling and downregulation of certain immune pathways are promising factors to identify NDBE with high risk of malignant progression. This thesis largely focuses on the inhibition of tumor growth and development of metastasis of EAC cells. Hereto, we used novel llama derived single domain antibodies (VHHs), which are directed against the Bone Morphogenetic Proteins: BMP2 and BMP4. Multiple in vitro and in vivo models were established to explore and validate the effect of VHHs on inhibiting the malignant behavior in EAC. This thesis found that in mouse models targeting BMP2/4 with our novel anti-BMP2/4 VHHs is an attractive molecular therapy for inhibition of tumor growth and prevention of metastasis in EAC. Further studies on clinical trials are warranted.