Optical imaging of pancreas cancer organoids for drug development and personalized treatment

胰腺癌类器官的光学成像用于药物开发和个性化治疗

• 批准号: 9388210
• 负责人: Melissa Caroline Skala
• 金额: $ 64.84万
• 依托单位: MORGRIDGE INSTITUTE FOR RESEARCH, INC.
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-01 至 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9388210
• 关键词: Adjuvant; Architecture; Biopsy; Biopsy Specimen; Caring; Cell Communication; Cells; Cessation of life; Clinical Trials; Data; Development; Development Plans; Dimensions; Disease; Drug Delivery Systems; Drug Monitoring; Drug Tolerance; Drug resistance; Early Diagnosis; Enzymes; Fibroblasts; Fluorescence; Goals; Gold; Human; Image; Imaging technology; Individual; Malignant Neoplasms; Malignant neoplasm of pancreas; Mass Spectrum Analysis; Metabolic; Modeling; Monitor; Morbidity - disease rate; Mus; NADH; Neoplasm Metastasis; Operative Surgical Procedures; Optics; Organoids; Pancreatic Ductal Adenocarcinoma; Patients; Pharmaceutical Preparations; Population Density; Preclinical Drug Evaluation; Prediction of Response to Therapy; Primary Neoplasm; Progression-Free Survivals; Regimen; Sampling; Stromal Cells; Stromal Neoplasm; Suspensions; System; Techniques; Technology; Testing; Time; Toxic effect; Treatment Efficacy; Tumor Volume; base; cancer imaging; cell type; chemotherapy; cohort; drug development; imaging approach; improved; improved outcome; in vivo; inhibitor/antagonist; metabolic imaging; mortality; mouse model; neoplastic cell; novel; novel therapeutics; optical imaging; outcome forecast; personalized medicine; predictive of treatment response; response; single cell analysis; standard measure; standard of care; three dimensional cell culture; tool; treatment planning; tumor

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive and poorly understood disease that has the worst prognosis of all cancers (5 year survival of 7%), with more than 40,000 deaths per year in the US. Standard- of-care treatment for PDAC includes surgery and chemotherapy. Many patients receive chemotherapy after surgery (“adjuvant treatment”), to improve progression-free survival. About 45-55% of patients present with metastatic disease and immediately begin chemotherapy if tolerated. Unfortunately, there are significant toxicities associated with chemotherapy, and there are no tools to determine whether a patient will benefit from a more toxic versus a less toxic drug. Additionally, there is no rational system to match each patient with the most promising new drug for their cancer. Finally, there are few effective drugs for PDAC, and therefore a demand for accelerated drug development. Thus, there is a critical need to improve the care of PDAC patients through reduced toxicities, rational treatment planning, and new drug development. The goal of this proposal is to develop novel cellular-level imaging technologies to predict treatment response in individual PDAC patients, using macro-suspensions of the patients’ tumors maintained in a 3D culture (“organoids”). This non-invasive optical metabolic imaging (OMI) approach exploits the intrinsic fluorescence intensity and lifetime of the metabolic co-enzymes NADH and FAD to image drug response on a single-cell level across all cells in the intact 3D sample. This single-cell analysis allows for heterogeneous drug response to be monitored over a treatment time-course in tumor cells and stromal cells. This is important for assessing treatment efficacy in the highly heterogeneous and stromal micro-environment of PDAC. The use of primary tumor organoids derived from the patients’ own tumor also maintains the cell-cell communication, 3D architecture, and tumor-stromal interactions that are critical to accurately assess drug response. Our preliminary data indicate that OMI in primary PDAC organoids (1) accurately predicts in vivo drug response in mice, and (2) can identify drugs that effectively target tumor fibroblasts for stromal re-organization and improved drug delivery. We have also established feasibility for human testing in 6 PDAC patients. This novel platform provides great potential for (1) rapidly testing new drug regimens on relevant patient samples, thus accelerating PDAC drug development, and (2) providing individualized drug screens to identify the most effective and least toxic treatment for each patient. This proposal will test the hypothesis that OMI of primary PDAC organoids can accurately predict in vivo treatment efficacy in mice and humans. This approach will be validated on mouse models of PDAC, on primary patient samples in the adjuvant treatment setting, and on primary patient samples in the metastatic treatment setting. The proposed development of dynamic, single-cell assessment techniques to monitor drug response in multiple cell types within intact mouse and human PDAC organoids holds great promise for rational drug development and treatment planning that could ultimately reduce toxicities and improve outcomes in patients.

胰腺导管腺癌（PDAC）是一种具有侵略性且知识渊博的疾病 所有癌症的最糟糕预后（5年生存期7％），美国每年有40,000多人死亡。标准- PDAC的护理治疗包括手术和化学疗法。许多患者在 手术（“辅助治疗”），以提高无进展生存率。大约45-55％的患者 转移性疾病并立即开始化学疗法。不幸的是，有重要的 与化学疗法相关的毒性，没有任何工具来确定患者是否会从中受益 与毒性较小的药物更具毒性。此外，没有理性的系统可以使每个患者与 最有前途的新药来治疗其癌症。最后，PDAC的有效药物很少，因此 对加速药物开发的需求。这是提高PDAC患者护理的迫切需要 通过降低毒性，理性的治疗计划和新药物开发。 该建议的目的是开发新型的细胞级成像技术来预测治疗反应 在个别PDAC患者中，使用3D培养的患者肿瘤的宏观求解 （“类器官”）。这种非侵入性光学代谢成像（OMI）方法利用了内在的荧光 代谢共生酶NADH和FAD的强度和寿命以单细胞水平对药物反应进行成像 在完整的3D样品中的所有细胞中。这种单细胞分析允许异质药物反应为 在肿瘤细胞和基质细胞中的治疗时间过程中受到监测。这对于评估治疗很重要 PDAC的高度异质和基质微环境的功效。原发性肿瘤的使用 从患者自己的肿瘤中得出的类器官还保持细胞 - 细胞通信，3D结构和 对于准确评估药物反应至关重要的肿瘤相互作用。我们的初步数据表明 原代PDAC器官（1）中的OMI准确地预测了小鼠体内药物反应，并且（2）可以鉴定药物 这有效地靶向肿瘤成纤维细胞进行基质重组织和改善药物递送。我们也有 在6名PDAC患者中确定了人类测试的可行性。这个小说平台为（1）提供了巨大的潜力 快速测试有关相关患者样品的新药物方案，从而加速PDAC药物的开发和 （2）提供个性化的药物筛查，以确定每位患者最有效，最毒性的治疗方法。 该提案将检验以下假设：主要PDAC类器官的OMI可以准确预测体内 小鼠和人类的治疗效率。这种方法将在PDAC的鼠标模型上进行验证 在调整治疗环境中的患者样品以及转移治疗中的主要患者样本 环境。提出的动态，单细胞评估技术的开发以监测药物反应 完整的小鼠和人PDAC器官中的多种细胞类型对有理药物有很大的希望 开发和治疗计划最终可以降低毒性并改善患者的预后。