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%。令人担忧的是， 食道癌的发病率在过去30年显著上升。EAC源于 已知的前驱病变，称为巴雷特食管（BE），在内窥镜检查中很容易识别。然而，在这方面， 目前的筛查和监测的临床策略是不够的，EAC的诊断往往发生在 疾病的晚期和不可切除的阶段。退伍军人是增加风险的BE和EAC相比， 由于风险因素增加，一般人群（包括年龄>50岁和男性）。有一个紧急临床 需要改进BE和EAC的检测、诊断和治疗策略。这种平移 研究计划旨在阐明EAC的分子致癌作用，最终目标是减少 与这种致命癌症有关的负担。 我们使用综合计算和遗传分析来确定共同的机制， EAC肿瘤进展。我们发现，与非恶性肿瘤相比，TGFβ通路在EAC中高度活跃。 是. TGFβ/Smad通路在上皮细胞中具有肿瘤抑制特性，包括抑制细胞增殖， 增殖和诱导细胞凋亡，功能性TGFβ途径元件经常通过 胃肠道恶性肿瘤的突变。然而，在已建立的癌症中，TGFβ信号传导可以促进侵袭， 和转移，表明TGFβ信号转导的相反作用取决于疾病阶段。相比之下，我们 初步研究结果表明，TGFβ通路不能抑制癌前发育不良BE细胞的生长， 相反，TGFβ诱导EAC细胞的生长，即使在功能性 TGFβ通路组分。此外，促肿瘤发生TGFβ途径作用在EAC中是明显的， 野生型或Smad 4突变体，Smad 4是TGFβ信号传导的典型介质。我们的初步研究 通过非常规Smad 4的早期过度激活来保护致癌TGFβ的替代模型 Smad 2/3依赖性通路。 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 EAC致癌中致癌TGFβ信号传导的决定因素。在目标2中，我们将评估 在高度相关的EAC临床前模型中破坏致癌TGFβ信号传导。尤其重要的是， LY 2157299（galunisertib）是一种口服生物可利用的TGFβ受体1型小分子抑制剂， 目前正在其他恶性肿瘤的II期试验中进行测试，代表了一种新的治疗策略， 对这种致命的癌症进行快速评估 这项研究具有高度创新性，将提高我们预防和治疗癌症的能力。 食道这里所述的科学建议和职业发展活动将发挥重要作用 在我作为VA临床胃肠病学家和科学家的发展过程中， 改善胃肠癌的早期发现和治疗。通过这个CDA-2奖项，我将获得 与癌症生物学，系统生物学和人类临床前模型相关的额外培训和经验 这对我实现目标至关重要此外，在这个丰富的指导环境中，我将培养技能， 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.