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

项目总结摘要 本申请是对特别利益通知(NOSI)的回应，该通知被标识为“非-- 食道癌(EC)是全球第六大癌症死亡原因，占全球癌症死亡人数的5%。 一年存活率为20%。食管癌的两种主要亚型：食管鳞癌和食管鳞癌 食管腺癌(EAC)对标准护理的敏感性明显不同 食道切除前的新辅助方案，包括化疗和放化疗，以及辅助方案 残留疾病的免疫治疗方案。鉴于它们对治疗的不同敏感性，有一个 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 对于每一种组织学，历史上都被视为一种单一的疾病。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，它在 而在EAC细胞系中则不表达。P63是一种已知的细胞代谢调节剂，具有 在促进糖酵解和氧化还原动态平衡方面的既定作用 鳞状细胞瘤，而p63的缺失会导致葡萄糖耐量降低和代谢综合征。我们 目的确定p63在食管癌和食管癌组织学基础上的代谢程序中的作用。 为了确定他们独特的代谢脆弱性并确定新的治疗靶点，朝着更 食道癌的个体化治疗方法。通过建议的具体目标和职业 发展计划，我们将通过定义ESCC和EAC的代谢途径来量化通量 确定它们对p63异构体表达的依赖性，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，我们将根据新陈代谢组谱对这些结果进行验证 治疗--单纯的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 用切割-运行和转录组学方法研究p63异构体在食管癌细胞系和有机体中的表达 使用多组学方法分析和整合这些数据集，以定义代谢网络 在P63的下游。研究将在2D和3D培养中进行，使用已建立的细胞系和患者- 衍生有机化合物，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，以及在概括原生建筑的新型3D培养模型中的多组学集成 以及人类食道癌和食道癌的生理学。这些研究的结果将提供新的 洞察ESCC和EAC的独特代谢脆弱性，这些脆弱性是其敏感性和抵抗力的基础 表型，并将为未来的研究提供基础，以建立新的代谢靶点用于治疗 这种致命的疾病。

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.