TGFβ and Smad Signaling Components in Esophageal Adenocarcinoma

食管腺癌(EAC)是一种高度致命的癌症，5年生存率低于20%。令人震惊的是， 在过去的30年里，食道癌的发病率显著增加。EAC起源于一个 已知的前驱病变，称为巴雷特食道(BE)，可以很容易地在内窥镜下识别。然而， 目前的临床筛查和监测策略不足，EAC诊断经常发生在 疾病的晚期和无法切除的阶段。与退伍军人相比，退伍军人BE和EAC的风险更高 由于风险因素(包括年龄和男性)增加而导致的一般人群。有一个紧急的临床 需要改进BE和EAC的检测、预测和治疗策略。此翻译 研究建议旨在阐明EAC的分子致癌机制，最终目标是减少 与这种致命癌症相关的负担。 我们使用综合的计算和遗传分析来确定共同的机制 EAC肿瘤进展。我们发现转化生长因子β通路在腹水癌中比在非恶性腹水癌中高度活跃。 就是这样。转化生长因子β/Smad通路在上皮细胞中具有肿瘤抑制作用，包括对细胞的抑制 增殖和诱导凋亡，以及转化生长因子β途径的功能元件经常通过 胃肠道恶性肿瘤中的突变。然而，在已建立的癌症中，转化生长因子β信号可以促进侵袭。 和转移，提示转化生长因子β信号转导的相反作用依赖于疾病的阶段。相比之下，我们的 初步研究结果表明，转化生长因子β通路不能抑制癌前发育不良的BE细胞的生长 相反，转化生长因子β即使在功能性细胞存在的情况下也能诱导肿瘤细胞的生长。 转化生长因子β途径成分。此外，促肿瘤转化生长因子β途径的作用在腹水癌中是明显的。 Smad4的野生型或突变型，Smad4是转化生长因子β信号的典型介导者。总之，我们的初步研究 用非常规的Smad4基因的早期过度激活来保护致癌转化生长因子β的替代模型 独立的，Smad2/3依赖的途径。 我们的发现具有重要的翻译意义。在目标1中，我们将研究分子 癌基因转化生长因子β信号在食管癌发生中的决定因素。在目标2中，我们将评估 在高度相关的EAC临床前模型中干扰致癌转化生长因子β信号。尤其重要的是， LY2157299(Galunisertib)是一种口服生物利用的转化生长因子β受体1型小分子抑制剂， 目前正在其他恶性肿瘤的第二阶段试验中测试，并代表了一种新的治疗策略，可以 对这种致命的癌症进行快速评估。 这项研究具有很高的创新性，将提高我们预防和治疗癌症的能力。 食管。这里描述的科学提案和职业发展活动将起到至关重要的作用 在我作为退伍军人事务部临床胃肠病专家和科学家的发展过程中，我的研究项目旨在 提高胃肠癌的早期发现和治疗水平。通过这个CDA-2奖项，我将获得 关于癌症生物学、系统生物学和人类临床前模型的其他培训和经验 癌症对于实现我的目标是必不可少的。此外，在这个丰富的指导环境中，我将发展技能 需要进行独立研究。

Esophageal adenocarcinoma (EAC) is a highly fatal cancer with 5-year survival under 20%. Alarmingly, the incidence of cancer of the esophagus has increased significantly over the past 30 years. EAC arises from a known precursor lesion, termed Barrett's esophagus (BE), that can be easily recognized at endoscopy. However, current clinical strategies of screening and surveillance are inadequate and EAC diagnosis often occurs at advanced and unresectable stages of the disease. Veterans are increased risk for BE and EAC compared to the general population due to increased risk factors (including age >50 and male gender). There is an urgent clinical need to improve strategies for the detection, prognostication, and treatment of BE and EAC. This translational research proposal aims to elucidate the molecular carcinogenesis of EAC, with the ultimate goal of reducing the burden associated with this deadly cancer. We used integrative computational and genetic analyses to identify common mechanisms that underlie EAC tumor progression. We identified that the TGFβ pathway is highly active in EAC compared to non-malignant BE. The TGFβ/Smad pathway has tumor suppressive properties in epithelial cells, including inhibition of cell proliferation and induction of apoptosis, and the functional TGFβ pathway elements are frequently lost through mutation in gastrointestinal malignancies. However, in established cancers TGFβ signaling can promote invasion and metastasis, suggesting opposing roles for TGFβ signaling that depend on disease stage. In contrast, our preliminary findings show that the TGFβ pathway fails to inhibit the growth of pre-malignant dysplastic BE cells in addition to EAC cells; on the contrary TGFβ induces growth of EAC cells even in the presence of functional TGFβ pathway components. Further, the pro-tumorigenic TGFβ pathway effects are evident in EAC that are either wild-type or mutant for Smad4, a canonical mediator of TGFβ signaling. Together, our preliminary studies indemnify an alternative model for the oncogenic TGFβ with early hyperactivation of an unconventional, Smad4 independent, Smad2/3 dependent pathway. Our findings have important translational implications. In Aim 1, we will investigate the molecular determinants of the oncogenic TGFβ signaling in EAC carcinogensis. In Aim 2, we will assess impact of disrupting oncogenic TGFβ signaling in highly relevant pre-clinical models of EAC. Of particular importance, LY2157299 (galunisertib), an orally bioavailable small molecule inhibitor of the TGFβ Receptor – Type 1, is currently being tested in Phase II trials in other malignancies and represents a new therapeutic strategy that can be rapidly evaluated for this lethal cancer. This study is highly innovative and will improve our ability to both prevent and treat cancer of the esophagus. The scientific proposal and career development activities described here will serve an essential role in my development as a clinical gastroenterologist at the VA and as a scientist with research program aimed at improving early detection and treatment of gastrointestinal cancer. Through this CDA-2 award, I will receive additional training and experience related to cancer biology, systems biology, and pre-clinical models of human cancer that will be essential to reach my goal. Also, in this rich mentored environment, I will develop skills required to perform independent research.