The role of AXL-ABL axis in Barrett's carcinogenesis

 描述(申请人提供)：食管腺癌(EAC)是一种侵袭性癌症，对现有治疗方法具有内在抵抗力，临床结果较差。胃食道反流病(GERD)是一种慢性病理状况，即食道暴露在酸性胃液和胆盐的混合环境中，是Barrett‘s食道的主要危险因素，Barrett’s食道是一种腺化生，发展为食管腺癌的风险很高。我们的初步数据表明，Axl是一种有利于生存的蛋白质，可以保护癌细胞免受遗传毒性DNA损伤事件的影响，如暴露于酸性胆盐和化疗药物中。基于这些新的初步数据，我们计划研究Axl在介导遗传毒性酸性胆盐和DNA损伤药物反应中的机制和生物学作用，并确定Axl在EAC中的临床和治疗潜力。在初步数据的支持下，我们假设P53的缺失介导了AXL蛋白在EAC中的上调。Axl的过表达通过调节核内和胞内c-ABL的蛋白水平来提供重要的促生存、促侵袭和恶性转化活性，以响应遗传毒性应激。这一假说将通过三个特定的目标来验证：1)研究P53在调节Ax1蛋白水平中的作用；2)研究AX在Barrett‘s和EAC细胞中调节c-ABL功能的作用；3)确定Ax1在EAC中的临床意义和治疗潜力。在目标1中，我们将研究P53负性调节Ax1蛋白表达的分子机制。在目标2中，将进行研究，以确定Axl在调节胞浆c-abl蛋白表达和稳定性中的作用。此外，还将研究Axl在调节c-ABL依赖的细胞存活、侵袭和恶性转化中的作用。在目标3中，将进行一项全面的研究，利用正常、癌前和EAC组织芯片的IHC分析，检测与人EAC中Ax1和c-abl蛋白表达相关的临床和组织病理学参数。此外，AXL作为治疗靶点的潜力将被评估为使用AXL抑制剂R428/BGB324或单独基因敲除，或在临床前环境中与顺铂、多西紫杉醇或奥沙利铂联合使用(异种小鼠模型)。这种方法是创新的，因为它基于一个创新的假设，即AXL-ABL轴在Barrett的致癌过程中发挥重要作用，AXL和c-ABL的机制研究与它们的联合致癌功能有关，先进的方法学，以及在EAC中新型靶向治疗的潜在开发。这项研究具有重要意义，因为它填补了我们对Axl在EAC中功能的理解的一个关键空白。在拟议的研究完成后，我们将对EAC的生物学有更好的了解，这将提供新的翻译机会，促进更好的治疗和预后方法的发展。

 DESCRIPTION (provided by applicant): Esophageal adenocarcinoma (EAC) is an aggressive carcinoma with intrinsic resistance to current therapies and poor clinical outcome. Gastro esophageal reflux disease (GERD), a chronic pathological condition in which the esophagus is exposed to acidic gastric juice mixed with bile salts, is the main risk factor for the development of Barrett's esophagus, a glandular metaplasia that carries a high risk for progression to esophageal adenocarcinoma. Our preliminary data has shown that AXL is a pro-survival protein that protects cancer cells against genotoxic DNA damaging events such as exposure to acidic bile salts and chemotherapeutics. Based on these novel preliminary data, we plan to investigate the mechanistic and biological roles of AXL in mediating response to genotoxic acidic bile-salts and DNA damaging drugs, and determine the clinical and therapeutic potential of AXL in EAC. Supported by preliminary data, we hypothesize that loss of p53 mediates up-regulation of AXL protein in EAC. The overexpression of AXL provides important pro-survival, pro-invasion, and malignant transformation activities by regulating the protein levels of both nuclear and cytosolic c-ABL in response to genotoxic stress. This hypothesis will be tested by pursuing three specific aims: 1) Investigate the role of p53 in regulating AXL protein level; 2) Investigate the role of AX in regulating c-ABL function in Barrett's and EAC cells; 3) Determine the clinical significance and therapeutic potential of AXL in EAC. In Aim 1, the molecular mechanisms by which p53 negatively regulates AXL protein expression will be investigated. In Aim 2, studies will be undertaken to determine the role of AXL in regulating cytosolic c-ABL protein expression and stability. Additionally, the role of AXL in regulating c- ABL-dependent cell survival, invasion, an malignant transformation will be examined. In Aim 3, a comprehensive study will be undertaken to examine the clinical and histopathological parameters associated with AXL and c-ABL protein expressions in human EAC, using IHC analysis of normal, premalignant, and EAC tissue microarrays. Also, the potential of AXL as a therapeutic target will be evaluated using the AXL inhibitor R428/BGB324 or genetic knockdown alone, or in combination with cisplatin, docetaxel, or oxaliplatin in pre- clinical settings (xenograft mouse model). The approach is innovative because it is based on an innovative hypothesis that proposes the AXL-ABL axis as an important player in Barrett's carcinogenesis, mechanistic studies of AXL and c-ABL relevant to their combined tumorigenic functions, advanced methodologies, and the potential development of novel targeted therapy in EAC. The proposed research is significant because it fills in a critical gap in our understanding of the functions of AXL in EAC. Upon completion of the proposed research, we will have a better understanding of the biology of EAC which could provide new translational opportunities that facilitate the development of better therapeutic and prognostic approaches.