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

 描述（由申请方提供）：食管腺癌（EAC）是一种侵袭性癌，对当前治疗具有内在耐药性，临床结局较差。胃食管反流病（GERD）是一种慢性病理状态，其中食管暴露于与胆盐混合的酸性胃液，是Barrett食管发展的主要风险因素，Barrett食管是一种腺化生，具有进展为食管腺癌的高风险。我们的初步数据表明，AXL是一种促生存蛋白，可保护癌细胞免受遗传毒性DNA损伤事件，如暴露于酸性胆汁盐和化疗药物。基于这些新的初步数据，我们计划研究AXL在介导对遗传毒性酸性胆汁酸盐和DNA损伤药物的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。初步数据的支持下，我们推测，p53的损失介导的AXL蛋白在EAC的上调。AXL的过表达通过调节细胞核和胞质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。该假设将通过追求三个具体目标来测试：1）研究p53在调节AXL蛋白水平中的作用; 2）研究AX在调节Barrett和EAC细胞中的c-ABL功能中的作用; 3）确定AXL在EAC中的临床意义和治疗潜力。在目的1中，p53负调控AXL蛋白表达的分子机制将被研究。在目标2中，将进行研究以确定AXL在调节胞质c-ABL蛋白表达和稳定性中的作用。此外，将检查AXL在调节c-ABL依赖性细胞存活、侵袭、恶性转化中的作用。在目标3中，将进行一项全面的研究，以检查临床和组织病理学参数与AXL和c-ABL蛋白表达在人类EAC，使用正常，癌前病变，和EAC组织微阵列的IHC分析。此外，在临床前环境中（异种移植小鼠模型），将使用AXL抑制剂R428/BGB 324或基因敲减单独或与顺铂、多西他赛或奥沙利铂联合评价AXL作为治疗靶标的潜力。该方法是创新的，因为它是基于一个创新的假设，提出了AXL-ABL轴作为一个重要的球员在巴雷特的致癌作用，机制研究AXL和c-ABL相关的联合致瘤功能，先进的方法，和新的靶向治疗的EAC的潜在发展。这项研究意义重大，因为它填补了我们对EAC中AXL功能的理解的关键空白。在完成拟议的研究后，我们将更好地了解EAC的生物学，这可以提供新的转化机会，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.