Project 3 - Genome-Guided Therapeutic Vulnerabilities in Esophageal Cancer

项目 3 - 基因组引导的食管癌治疗脆弱性

• 批准号: 10214546
• 负责人: Adam Joel Bass
• 金额: $ 16.7万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-08-15 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10214546
• 关键词: 3-Dimensional; Adenocarcinoma; Affect; Biological Markers; CCND1 gene; CCNE1 gene; CDK2 gene; CDK4 gene; Cell Cycle; Cells; Cessation of life; Chromosomal Instability; Clinical; Collaborations; Combined Modality Therapy; Core Facility; Cyclin D1; Cyclins; Cytotoxic T-Lymphocytes; Data; Development; ERBB2 gene; Engineering; Environment; Epidermal Growth Factor Receptor; Epithelial; Esophageal Adenocarcinoma; Esophageal Squamous Cell Carcinoma; Esophagus; Flow Cytometry; Funding; Gene Amplification; Genes; Genome; Genome Stability; Genomics; Glutaminase; Goals; Immune; Immune Evasion; Immune checkpoint inhibitor; Immunocompetent; Immunofluorescence Immunologic; Immunologics; Immunotherapy; Innovative Therapy; Malignant Neoplasms; Malignant neoplasm of esophagus; Mediating; Mediator of activation protein; Modeling; Mus; Oncogenes; Organoids; Pathologic; Phosphotransferases; Publications; Receptor Protein-Tyrosine Kinases; Role; Squamous cell carcinoma; T-Lymphocyte; Technology; Testing; Therapeutic; Tumor Escape; Work; anti-tumor immune response; base; biomarker-driven; cancer genome; cancer genomics; cancer therapy; esophageal carcinogenesis; immunoengineering; inhibitor/antagonist; neoplastic cell; novel; novel therapeutics; optimal treatments; overexpression; replication stress; single-cell RNA sequencing; synergism; tumor; tumor microenvironment; tumorigenesis

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.

项目摘要 – 项目 3 食管癌导致超过 40 万人死亡，迫切需要新疗法 每年。在此，我们建议以我们之前的研究为基础，以我们的观察为基础 食管癌（包括鳞状细胞癌 (ESSC) 和 腺癌 (EAC) 是编码细胞周期介质的基因的扩增，例如 CCND1=细胞周期蛋白D1（与项目3合作）和CCNE1=细胞周期蛋白E1和编码受体酪氨酸的基因 EGFR（与项目 1 合作）和 ERBB2 等激酶。鉴于这种基因组景观，一个关键 我们工作的前提是开发将两种活性靶点结合起来的治疗方法 激酶和细胞周期失调将非常有益。虽然这些数据、假设和前提 所有这些都继续成立，我们现在提出对细胞周期失调如何可能进行更细致的评估 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 的过度表达会对肿瘤微环境产生影响。 基因组稳定性，两者对最佳治疗都有明显的影响。这个假设将被追求 通过以下相互关联的具体目标： (1) 确定 CDK4/6 抑制剂如何影响肿瘤 CCND1 扩增的食管鳞状细胞癌的微环境并定义增强的免疫 治疗策略； (2) 为了阐明 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避。总之，这些研究将帮助我们 为这些致命的癌症开发基本原理、生物标志物引导的疗法。这项工作将在密切的情况下完成 与项目 1 和 2 合作，推动演示、出版物并改变临床景观 食管癌，并以与其他项目综合的方式利用核心设施。