Project 3 - Genome-Guided Therapeutic Vulnerabilities in Esophageal Cancer

项目概要-项目3 食管癌的新疗法是迫切需要的，这是负责> 40万人死亡 每年。在此，我们建议建立在我们先前研究的基础上，基于我们的观察， 食管癌（鳞状细胞癌（ESSC）和 腺癌（EAC）是编码细胞周期介质的基因的扩增，例如 CCND 1 =细胞周期蛋白D1（与项目3合作）和CCNE 1 =细胞周期蛋白E1和编码受体酪氨酸的基因 激酶，如EGFR（与项目1合作）和ERBB 2。鉴于这种基因组格局， 我们工作的前提是，开发整合靶向两种活性药物的治疗方法， 激酶和细胞周期失调将是非常有益的。虽然这些数据、假设和前提 所有这些仍然是正确的，我们现在提出一个更微妙的评估细胞周期失调如何可能 影响肿瘤发生和最佳癌症治疗。具体来说，我们假设放大和 Cyclin D1和Cyclin E1的过表达可以影响肿瘤微环境， 基因组稳定性，这两者对最佳治疗有明确的意义。我们将继续研究这一假设。 通过以下相互关联的具体目的：（1）确定CDK 4/6抑制剂如何影响肿瘤 CCND 1扩增的食管鳞状细胞癌的微环境，并确定增强的免疫 为了阐明CCNE 1扩增如何促进染色体不稳定性，激酶 扩增和免疫逃避。这些研究将帮助我们 为这些致命的癌症开发合理的、生物标志物引导的疗法。这项工作将在密切 与项目1和项目2合作，推动演讲、出版和改变临床景观， 食管癌，并与其他项目综合利用核心设施。

PROJECT SUMMARY – PROJECT 3 New therapies are desperately needed for esophageal cancer, which is responsible for >400,000 deaths annually. Herein we propose to build on momentum from our prior studies, founded on our observation that the most prominent genomic targets in esophageal cancer, both squamous cell carcinoma (ESSC) and adenocarcinoma (EAC), are amplifications of genes encoding mediators of the cell cycle such as CCND1=Cyclin D1 (collaboration with Project 3) and CCNE1=Cyclin E1 and genes encoding receptor tyrosine kinases such as EGFR (collaboration with Project 1) and ERBB2. Given this genomic landscape, a key premise of our work has been that developing therapeutic approaches that integrate targeting of both active kinases and cell cycle dysregulation will be remarkably beneficial. While these data, hypotheses and premises all continue to hold true, we now propose a more nuanced assessment of how cell cycle dysregulation may impact tumorigenesis and optimal cancer therapy. Specifically, we hypothesize that amplification and overexpression of Cyclin D1 and Cyclin E1 can have effects upon the tumor microenvironment and upon genomic stability, both of which have clear implications for optimal therapy. This hypothesis will be pursued through the following interrelated Specific Aims: (1) To determine how CDK4/6 inhibitors impact the tumor microenvironment in CCND1-amplified esophageal squamous cell carcinoma and to define enhanced immune therapy strategies; and (2) To elucidate how CCNE1 amplification promotes chromosomal instability, kinase amplification and immune evasion in esophageal adenocarcinoma. Together, these studies will help us develop rationale, biomarker-guided therapies for these deadly cancers. This work will be done in close collaboration with Projects 1 and 2 to drive presentations, publications and transform the clinical landscape of esophageal cancer, and to utilize the core facilities in an integrated fashion with the other Projects.