Administrative Supplements to Participate in the NCI Early-stage Surgeon Scientist Program (ESSP)

参加 NCI 早期外科医生科学家计划 (ESSP) 的行政补充

• 批准号: 10749648
• 负责人: LAURIE Hollis GLIMCHER
• 金额: $ 20.88万
• 依托单位: DANA-FARBER CANCER INST
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-03-10 至 2026-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10749648
• 关键词: Acids; Acute; Adenocarcinoma; Adenocarcinoma Cell; Adjuvant; Adjuvant Study; Administrative Supplement; Africa; Alcohols; Architecture; Asia; Barrett Esophagus; Bile fluid; Biochemical Pathway; Bioenergetics; Biological Assay; Biopsy Specimen; Cancer Etiology; Cancer cell line; Carbon; Carboplatin; Cell Differentiation process; Cell Line; Cell Proliferation; Cessation of life; Chemotherapy and/or radiation; Chromatin; Chronic; Citric Acid Cycle; Country; Data; Data Set; Dependence; Development; Development Plans; Disease; Distant; Early Diagnosis; Embryonic Development; Enzymes; Epithelial Cells; Esophageal Adenocarcinoma; Esophageal Squamous Cell; Esophageal Squamous Cell Carcinoma; Esophagectomy; Esophagus; Excision; Future; Gastroesophageal reflux disease; Gene Expression; Gene Expression Profiling; Genes; Genomics; Glucose; Glucose Intolerance; Glutamine; Glycolysis; High Prevalence; Histologic; Histology; Homeostasis; Human; Immunotherapy; Inflammation; Inflammatory; K-Series Research Career Programs; Knowledge; Large Intestine Carcinoma; Liquid substance; Lye; Malignant - descriptor; Malignant Neoplasms; Malignant neoplasm of esophagus; Malignant neoplasm of gastrointestinal tract; Malignant neoplasm of pancreas; Mediator; Metabolic; Metabolic Pathway; Metabolic stress; Metabolic syndrome; Metabolism; Methanol; Mission; Modality; Modeling; Molecular; Multiomic Data; NADP; Neoadjuvant Therapy; Neoplasm Metastasis; Obesity; Organoids; Oxidation-Reduction; Oxidative Phosphorylation; Oxidative Stress; Paclitaxel; Pathway interactions; Patients; Phenotype; Physiology; Principal Investigator; Process; Protein Isoforms; Protocols documentation; Public Health; Radiation; Recurrence; Regimen; Research Personnel; Residual Neoplasm; Resistance; Role; Scientific Advances and Accomplishments; Scientist; Signal Pathway; Squamous Cell; Squamous Cell Neoplasms; Squamous Differentiation; Squamous cell carcinoma; Starvation; Stress; Surgeon; System; Temperature; Testing; The Cancer Genome Atlas; Tissue Sample; Training; Treatment Protocols; Work; Writing; cancer subtypes; career development; cell growth; chemoradiation; chemotherapy; data integration; differential expression; effective therapy; esophageal squamous cell cancer; established cell line; fatty acid oxidation; functional genomics; histone modification; improved; individualized medicine; insight; interest; knock-down; liquid chromatography mass spectrometry; metabolic phenotype; metabolome; metabolomics; multiple omics; new therapeutic target; next generation; novel; overexpression; personalized medicine; programs; response; stable isotope; standard of care; surgery outcome; three dimensional cell culture; tobacco exposure; transcription factor; transcriptomics; treatment strategy

PROJECT SUMMARY ABSTRACT This application is being submitted in response to the Notice of Special Interest (NOSI) identified as "NOT- CA-21-100." Esophageal cancer (EC) is the sixth most common cause of cancer deaths worldwide, with 5- year survival of 20%. The two primary subtypes of EC, esophageal squamous cell carcinoma (ESCC) and esophageal adenocarcinoma (EAC), demonstrate markedly different sensitivities to standard-of-care neoadjuvant regimens, including chemotherapy and chemoradiation prior to esophagectomy, and adjuvant immunotherapy protocols for residual disease. Given their differential sensitivities to treatment, there is a critical need to identify the unique vulnerabilities of ESCC and EAC and develop tailored treatment regimens for each histology, which historically have been treated as a single disease. The transcription factor p63 is a marker of squamous cell differentiation, and our preliminary data have shown that it is highly expressed in ESCC cell lines and absent in EAC cell lines. P63 is a known regulator of cellular metabolism, with established roles in promoting glycolysis and redox homeostasis in both embryonic development and squamous cell tumors, while the absence of p63 results in glucose intolerance and metabolic syndrome. We aim to determine the role of p63 in defining metabolic programs that underlie ESCC and EAC histologies in order to define their unique metabolic vulnerabilities and identify novel therapeutic targets, towards a more personalized treatment approach for esophageal cancers. Through the proposed Specific Aims and Career Development Plan, we will quantify the flux through metabolic pathways that define ESCC and EAC and determine their dependence on p63 isoform expression, correlating these results with markers of squamous and glandular differentiation. Furthermore, we will validate these results against metabolome profiles of treatment-naïve ESCC and EAC tissue samples. In Aim 2, we will define direct and indirect metabolic targets of p63 isoforms in esophageal cancer cell lines and organoids using CUT-and-RUN and transcriptomics analyses, and integrate these datasets using multi-omics approaches to define the metabolic network downstream of p63. Studies will be performed in 2D and 3D cultures using established cell lines and patient- derived organoids, as well as patient-derived biopsy samples, and utilize functional genomics, high throughput metabolomics, and multi-omics integration in novel 3D culture models that recapitulate the native architecture and physiology of human esophagus and esophageal cancers. The results of these studies will provide novel insight into the unique metabolic vulnerabilities of ESCC and EAC that underlie their sensitivity and resistance phenotypes, and will provide the basis for future studies to establish new metabolic targets for treatment of this deadly disease.

项目摘要 本申请是为了回应被确定为“非- CA-21-100食管癌（EC）是全球第六大癌症死亡原因，其中5- 年生存率20%。EC的两种主要亚型，食管鳞状细胞癌（ESCC）和 食管腺癌（EAC）对标准治疗的敏感性明显不同 新辅助治疗方案，包括食管切除术前的化疗和放疗，以及辅助治疗 残留疾病的免疫治疗方案。鉴于他们对治疗的敏感性不同， 迫切需要确定ESCC和EAC的独特脆弱性，并制定量身定制的治疗方案 对于每种组织学，历史上一直被视为单一疾病。转录因子p63是一种 鳞状细胞分化的标志物，我们的初步数据表明，它是高度表达在 在ESCC细胞系中不存在，在EAC细胞系中不存在。P63是已知的细胞代谢调节剂， 在胚胎发育和发育过程中促进糖酵解和氧化还原稳态的作用， 鳞状细胞肿瘤，而缺乏p63导致葡萄糖耐受不良和代谢综合征。我们 旨在确定p63在确定ESCC和EAC组织学基础代谢程序中的作用， 为了确定他们独特的代谢脆弱性，并确定新的治疗目标，朝着一个更 食管癌的个性化治疗方法。通过提出的具体目标和职业 开发计划，我们将量化通过代谢途径的通量，定义ESCC和EAC， 确定它们对p63亚型表达的依赖性，将这些结果与鳞状细胞癌的标志物相关联， 和腺体分化。此外，我们将根据代谢组学特征验证这些结果， 初治ESCC和EAC组织样本。在目标2中，我们将定义直接和间接代谢目标 使用CUT-and-RUN和转录组学分析食管癌细胞系和类器官中的p63亚型 分析，并使用多组学方法整合这些数据集，以定义代谢网络 P63的下游。研究将在2D和3D培养中使用已建立的细胞系和患者- 衍生的类器官以及患者衍生的活检样本，并利用功能基因组学、高通量 代谢组学和多组学整合在新的3D培养模型，概括了天然结构 和人体食道和食道癌的生理学。这些研究结果将提供新的 深入了解ESCC和EAC独特的代谢弱点，这些弱点是其敏感性和抵抗力的基础 表型，并将提供基础，为未来的研究，以建立新的代谢目标，治疗 这种致命的疾病。