Randomized Placebo-Controlled Trial of a Gastrin Receptor Antagonist in Barretts Esophagus

 描述（由申请人提供）：在过去的几十年中，食管腺癌（EAC）的发病率上升了五倍，但EAC的预后仍然极差。因此，EAC是一个非常有吸引力的化学预防靶点。巴雷特食管（BE）是EAC的前驱病变，酸反流是BE和EAC的主要危险因素。几乎所有BE患者，无论是否存在反流，都用质子泵抑制剂治疗以抑制胃酸的产生。然而，质子泵抑制剂尚未最终显示可降低进展为EAC的风险。这可能是由于酸抑制导致胃中胃窦G细胞的胃泌素产生增加，并且胃泌素对BE组织具有许多促肿瘤作用，例如增加细胞增殖和考克斯-2表达以及抑制细胞凋亡。我们先前在BE患者中证明了高水平的血清胃泌素与高度异型增生和EAC相关，并且血清胃泌素水平与BE中的细胞增殖相关。总之，这些研究结果表明，胃泌素实际上可能促进巴雷特食管向食管腺癌的进展。Netazepide是一种新型的胃泌素受体拮抗剂，可有效地选择性阻断胃泌素的作用。在我们小组开发的BE和EAC小鼠模型的实验中，高胃泌素血症促进了肿瘤的进展，用奈他唑派治疗显著降低了细胞增殖， 肠干细胞标志物的表达和发育异常的发展。因此，我们假设胃泌素受体抑制可能会降低巴雷特患者进展为EAC的风险。直接建立在我们以前在这一领域的工作，我们已经设计并开始在22例BE患者中进行II期随机、双盲、安慰剂对照试验，以研究奈他唑派对与进展为EAC相关的生物标志物的影响。我们目前正在请求更多的支持，以便顺利完成这项审判 并实现以下具体目的：1）确定胃泌素受体拮抗剂奈他唑派是否减少Barrett食管患者的细胞增殖;和2）确定奈他唑派是否减少与进展为EAC相关的其它标志物的表达。通过这种方式，我们希望证明用胃泌素受体拮抗剂治疗巴雷特食管患者是一种新的和潜在的有效策略，以降低食管腺癌的风险。

 DESCRIPTION (provided by applicant): The incidence of esophageal adenocarcinoma (EAC) has risen five-fold over the past several decades, yet the prognosis for EAC remains extremely poor. As such, EAC represents a very attractive target for chemoprevention. Barrett's esophagus (BE) is the precursor lesion for EAC, and acid reflux is a major risk factor for both BE and EAC. Virtually all patients with BE, regardless of the presence of reflux, are treated with proton pump inhibitors to suppress the production of gastric acid. However, proton pump inhibitors have not conclusively been shown to reduce the risk of progression to EAC. This may be due to the fact that acid suppression results in increased gastrin production by antral G cells in the stomach, and gastrin has numerous proneoplastic effects on BE tissue, such as increasing cellular proliferation and COX-2 expression and inhibiting apoptosis. We have previously demonstrated in BE patients that high levels of serum gastrin are associated with high grade dysplasia and EAC, and serum gastrin levels are correlated with cellular proliferation in BE. Together, these findings suggest that gastrin may in fact promote the progression of Barrett's esophagus to esophageal adenocarcinoma. Netazepide is a novel gastrin receptor antagonist that effectively and selectively blocks the effects of gastrin. In experiments with a mouse model of BE and EAC that was developed by our group, hypergastrinemia promoted neoplastic progression, and treatment with netazepide significantly reduced cellular proliferation, expression of intestinal stem cell markers, and development of dysplasia. We therefore hypothesize that gastrin receptor inhibition may reduce the risk of progression to EAC in Barrett's patients. Building directly on our prior work in this field, we have designed and begun enrollment for a phase II randomized, double-blind, placebo-controlled trial in 22 patients with BE to investigate the effects of netazepide on biomarkers associated with progression to EAC. We are currently requesting additional support to allow for the successful completion of this trial and to achieve the following Specific Aims: 1) To determine whether the gastrin receptor antagonist netazepide reduces cellular proliferation in patients with Barrett's esophagus; and 2) To determine whether netazepide reduces the expression of other markers associated with progression to EAC. In this fashion we hope to demonstrate that treatment of Barrett's esophagus patients with a gastrin receptor antagonist represents a novel and potentially effective strategy to reduce the risk of esophageal adenocarcinoma.