Development of a precision medicine platform for circadian based therapeutics in pancreatic cancer

开发基于昼夜节律的胰腺癌精准医学平台

• 批准号: 10477631
• 负责人: Faraz Bishehsari
• 金额: $ 66.31万
• 依托单位: RUSH UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-21 至 2027-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10477631
• 关键词: Area; Bioinformatics; Biological Assay; Biological Markers; Biological Process; Biopsy; Cancer Etiology; Cell Line; Cessation of life; Chronotherapy; Circadian Rhythms; Clinic; Clinical; Clinical Protocols; Clinical Research; Clinical Trials; Code; DNA Repair; DNA biosynthesis; Data; Data Science; Detection; Development; Diagnosis; Disease; Dose; Effectiveness; Endoscopic Biopsy; Event; Excision; Genes; Goals; Heterogeneity; Hour; Human; Incidence; Individual; Knowledge; Legal patent; Link; Logistics; Machine Learning; Malignant Neoplasms; Malignant neoplasm of lung; Malignant neoplasm of pancreas; Maps; Medicine; Methods; Molecular; Molecular Abnormality; Molecular Profiling; Motivation; Operative Surgical Procedures; Organ; Organoids; Outcome; Pancreas; Pancreatic Ductal Adenocarcinoma; Pathologic; Pathway interactions; Patients; Pattern; Periodicity; Pharmaceutical Preparations; Pharmacotherapy; Phenotype; Precision therapeutics; Prognosis; Proteins; Research; Retroperitoneal Space; Role; Sampling; Shapes; Solid Neoplasm; Source; Testing; Therapeutic; Time; Tissues; Treatment Efficacy; Tumor Tissue; Variant; Work; base; cancer subtypes; cancer type; chemotherapy; circadian; circadian pacemaker; clinical application; clinical predictors; disease prognosis; drug efficacy; effective therapy; fighting; high reward; high risk; improved; innovation; insight; inter-individual variation; interest; malignant breast neoplasm; metastatic colorectal; next generation sequencing; novel; novel therapeutic intervention; pancreatic ductal adenocarcinoma cell; personalized approach; personalized medicine; pre-clinical; precision medicine; preclinical study; response; screening; side effect; standard of care; transcriptomics; treatment strategy; tumor

Abstract Pancreatic ductal adenocarcinoma (PDA) is among the most fatal of all cancers, and is on track to become the second-leading cause of cancer-related death in the US by 2030. There is significant heterogeneity among PDA tumors, mitigating the effectiveness of conventional chemotherapy and highlighting the need for more individualized approaches to treatment. Personalized medicine (PM) strategies, which take tumor and/or patient- specific data into account when deciding on a course of treatment, have shown great promise within the context of many different types of cancers in recent preclinical and clinical studies. However, most PM approaches rely on molecular profiling data that require relatively large samples of tumor tissue. Unlike other cancers in which surgical resection is standard-of-care, PDA patients rarely undergo surgery at diagnosis. In the absence of upfront surgery in the majority of PDA patients, access to sufficient tumor tissue for comprehensive molecular and drug profiling in PDA is limited. Patient-derived organoids (PDOs) represent a unique opportunity to circumvent this limitation. Patient-derived organoids can be successfully established from the scant tissue collected during endoscopic biopsies, which are routine in PDA diagnosis. Moreover, such organoids can recapitulate the phenotype of their tissue of origin and can predict patient drug response in clinic. The primary goal of the current proposal is to establish pre-clinical predictors of tumor-specific circadian clock dynamics and chronotherapeutic efficacy using normal human pancreas tissue, well characterized PDA cell lines and patient- specific biopsy-based PDOs. Specifically, we will: (1) characterize baseline molecular rhythms and clock dynamics in the normal human pancreas over 24 hours; (2) determine the role of PDA cancer events in tumor clock perturbations and patient survival and (3) validate the use of molecular and drug response profiling data from PDOs to inform time-based drug treatment (“chronotherapy”) strategies. Altogether, these studies will help advance the use of tumor specific circadian profiles in clinical settings, with particular implications for bringing more individualized and targeted time/circadian-based strategies to PDA patients.

抽象的 胰腺导管腺癌 (PDA) 是所有癌症中最致命的一种，并且有望成为最致命的癌症 到 2030 年，将成为美国癌症相关死亡的第二大原因。PDA 之间存在显着的异质性 肿瘤，降低了传统化疗的有效性，并强调需要更多 个体化治疗方法，个体化医疗（PM）策略，采用肿瘤和/或患者的治疗方法。 在决定治疗方案时考虑具体数据，在该背景下显示出巨大的希望 然而，大多数 PM 方法依赖于最近的临床前和临床研究。 与其他癌症不同，分子分析数据需要相对较大的肿瘤组织样本。 手术切除是标准治疗方法，PDA 患者在诊断时很少接受手术。 大多数 PDA 患者进行前期手术，可以获得足够的肿瘤组织进行全面的分子治疗 PDA 中的药物分析是有限的。 可以从稀缺的组织中成功建立患者来源的类器官。 在内窥镜活检期间收集，这是 PDA 诊断的常规方法。此外，此类类器官可以。 概括其起源组织的表型，并可以预测临床上患者的药物反应。 当前提案的目标是建立肿瘤特异性生物钟动态的临床前预测因子和 使用正常人胰腺组织、充分表征的 PDA 细胞系和患者的时间治疗功效 具体来说，我们将：（1）表征基线分子节律和时钟。 (2) 确定 PDA 癌症事件在肿瘤中的作用； 时钟扰动和患者生存率，以及 (3) 验证分子和药物反应分析数据的使用 总而言之，这些研究将有助于从 PDO 中获取基于时间的药物治疗（“时间疗法”）策略。 推进肿瘤特异性昼夜节律在临床环境中的使用，特别是对于带来 为 PDA 患者提供更加个性化和有针对性的时间/昼夜节律策略。