Project 3 - Genome-Guided Therapeutic Vulnerabilities in Esophageal Cancer

项目摘要--项目3 导致40万人死亡的食道癌亟需新的治疗方法 每年一次。在此，我们建议在我们之前的研究的基础上，基于我们的观察，建立在势头的基础上 食道癌中最显著的基因组靶点，包括鳞状细胞癌(ESSC)和 腺癌(EAC)是编码细胞周期介体的基因的放大，如 CCND1=Cyclin D1(与项目3合作)和CCNE1=Cyclin E1和编码受体酪氨酸的基因 例如EGFR(与项目1合作)和ERBB2等激酶。鉴于这一基因组图景，一把钥匙 我们工作的前提是开发结合了两种活性靶向的治疗方法 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 所有这些都是正确的，我们现在提出一种更细微的评估，以评估细胞周期失调可能 影响肿瘤发生和最佳癌症治疗。具体地说，我们假设这种放大和 细胞周期蛋白D_1和细胞周期蛋白E_1的过表达可影响肿瘤微环境 基因组稳定性，这两个因素对最佳治疗都有明显的影响。这一假说将继续下去。 通过以下相互关联的特定目的：(1)确定CDK4/6抑制剂如何影响肿瘤 CCND1扩增的食管鳞癌微环境与免疫增强的关系 治疗策略；以及(2)阐明CCNE1扩增如何促进染色体不稳定，激酶 食管腺癌的扩增和免疫逃逸总之，这些研究将帮助我们 为这些致命的癌症开发合理的、生物标记物引导的治疗方法。这项工作将近距离完成 与项目1和项目2协作，以推动演示文稿、出版物并改变 食道癌，并以综合方式利用核心设施和其他项目。

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.