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.

摘要