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腺癌之一，并有望成为 到2030年，美国与癌症相关死亡的第二个领先原因。PDA之间存在明显的异质性 肿瘤，降低常规化学疗法的有效性，并强调需要更多 个性化的治疗方法。个性化医学（PM）策略，该策略服用肿瘤和/或患者 - 确定治疗过程时考虑了具体数据 在最近的临床前和临床研究中，许多不同类型的癌症。但是，大多数PM方法都依赖 关于分子分析数据，需要相对较大的肿瘤组织样品。与其他癌症不同 手术切除是护理标准，PDA患者在诊断时很少接受手术。在没有 大多数PDA患者的前期手术，进入足够的肿瘤组织以进行全面的分子 PDA中的药物分析受到限制。患者衍生的类器官（PDOS）代表了一个独特的机会 规避此限制。可以从缺少组织中成功建立患者来源的类器官 在内窥镜活检中收集，这是PDA诊断中常规的。此外，这样的类型可以 概括其起源组织的表型，并可以预测诊所中的患者药物反应。主要 当前建议的目的是建立肿瘤特异性昼夜节律动态和 使用正常的人胰腺组织，PDA细胞系和患者 - 基于特定活检的PDO。具体来说，我们将：（1）表征基线分子节奏和时钟 正常人胰腺的动力学超过24小时； （2）确定PDA癌事件在肿瘤中的作用 时钟扰动和患者存活以及（3）验证分子和药物反应分析数据的使用 从PDO到基于时间的药物治疗（“计时疗法”）策略。这些研究总共有助于 在临床环境中推动使用特定肿瘤特异性昼夜节律的使用，对带来的影响 PDA患者的更多个性化和针对性的时间/昼夜节律策略。