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

摘要 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 到2030年，它将成为美国癌症相关死亡的第二大原因。PDA之间存在显著的异质性 肿瘤，减轻传统化疗的有效性，并强调需要更多的 个性化的治疗方法。个性化医疗（PM）策略，将肿瘤和/或患者- 在决定治疗过程时考虑具体数据，在这种情况下显示出很大的希望 在最近的临床前和临床研究中发现了许多不同类型的癌症。然而，大多数PM方法依赖于 需要相对较大的肿瘤组织样本的分子分析数据。与其他癌症不同， 手术切除是标准治疗，PDA患者很少在诊断时接受手术。在没有 在大多数PDA患者的前期手术中，可获得足够的肿瘤组织进行全面的分子生物学检查， 并且PDA中的药物分析是有限的。患者源性类器官（PDO）代表了一个独特的机会， 规避这个限制。患者来源的类器官可以成功地从缺乏的组织中建立 在PDA诊断中的常规内镜活检中收集。此外，这样的类器官可以 概括其来源组织的表型，并可以预测临床上患者的药物反应。主 当前提案的目标是建立肿瘤特异性生物钟动力学的临床前预测因子， 使用正常人胰腺组织、充分表征的PDA细胞系和患者的慢性功效， 基于活检的特定PDO。具体而言，我们将：（1）表征基线分子节律和时钟 正常人胰腺中24小时内的动力学;（2）确定PDA癌症事件在肿瘤中的作用 生物钟扰动和患者存活率，以及（3）验证分子和药物反应谱数据的使用 从PDO到告知基于时间的药物治疗（"时间疗法"）策略。总之，这些研究将有助于 在临床环境中推进肿瘤特异性昼夜节律谱的使用，特别是对 更个性化和有针对性的时间/昼夜节律为基础的策略，PDA患者。

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.