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癌症之一，有望成为 到2030年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 个体化的治疗方法。个性化医疗(PM)策略，将肿瘤和/或患者- 在决定疗程时考虑的具体数据在上下文中显示出巨大的前景 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 基于需要相对较大的肿瘤组织样本的分子图谱数据。与其他癌症不同的是 手术切除是标准的护理，PDA患者很少在确诊时进行手术。在没有的情况下 在大多数PDA患者的前期手术中，获得了足够的肿瘤组织进行全面的分子研究 而PDA中的药物分析是有限的。患者衍生的有机化合物(PDO)代表着一个独特的机会 绕过这一限制。从稀少的组织中可以成功地建立患者衍生的有机类化合物 在内窥镜活检中收集，这在PDA诊断中是常规的。此外，这种有机化合物可以 总结其起源组织的表型，并可在临床上预测患者的药物反应。初级阶段 当前提案的目标是建立肿瘤特异性昼夜节律动力学的临床前预测因子和 使用正常的人胰腺组织、具有良好特性的PDA细胞系和患者- 特定的基于活检的PDO。具体地说，我们将：(1)表征基线分子节律和时钟 正常人胰腺24小时内的动态变化；(2)确定PDA癌事件在肿瘤中的作用 时钟扰动和患者存活率，以及(3)验证分子和药物反应图谱数据的使用 从PDO到以时间为基础的药物治疗(“时间疗法”)战略。总之，这些研究将会有所帮助。 促进在临床环境中使用肿瘤特定的昼夜节律曲线，并对带来 为PDA患者提供更个性化和针对性的基于时间/昼夜节律的策略。

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.