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: 9769226
• 负责人: Melissa Caroline Skala
• 金额: $ 24.64万
• 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/9769226
• 关键词: 3-Dimensional; 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 Screening; 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; 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; cell type; chemotherapy; cohort; drug development; drug response prediction; imaging approach; improved; improved outcome; in vivo; inhibitor/antagonist; metabolic imaging; mortality; mouse model; neoplastic cell; novel; novel therapeutics; optical imaging; outcome forecast; patient response; personalized medicine; 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)是一种侵袭性强且知之甚少的疾病。 在所有癌症中预后最差(5年存活率为7%)，美国每年有超过40,000人死亡。标准- PDAC的护理治疗包括手术和化疗。许多患者在接受化疗后 手术(“辅助治疗”)，以提高无进展的存活率。约45%-55%的患者在场 如果耐受，立即开始化疗。不幸的是，有重要的 与化疗相关的毒性，而且还没有工具来确定患者是否将受益于 一种毒性更强的药物，而不是毒性更小的药物。此外，没有一个合理的系统来将每个患者与 最有希望的治疗癌症的新药。最后，治疗PDAC的有效药物很少，因此 对加快药物开发的需求。因此，迫切需要改善对pdac患者的护理。 通过减少毒性、合理的治疗计划和新药开发。 这项提议的目标是开发新的细胞级成像技术来预测治疗反应。 在个体PDAC患者中，使用维持在3D培养中的患者肿瘤的大悬浮液 (“有机化合物”)。这种非侵入性的光学代谢成像(OMI)方法利用了本征荧光 代谢辅酶NADH和FAD的强度和寿命在单细胞水平上成像药物反应 完整的3D样本中的所有细胞。这种单细胞分析允许异质药物反应 在治疗过程中对肿瘤细胞和间质细胞进行监测。这对于评估治疗很重要。 在PDAC高度异质和基质微环境中的疗效。原发肿瘤的应用 从患者自己的肿瘤中提取的有机化合物也保持了细胞之间的沟通，3D结构，以及 肿瘤-间质相互作用是准确评估药物反应的关键。我们的初步数据显示 初级PDAC有机化合物中的OMI(1)可以准确地预测小鼠体内的药物反应，(2)可以识别药物 有效地靶向肿瘤成纤维细胞进行间质重组和改善药物输送。我们还有 建立了在6例PDAC患者中进行人体试验的可行性。这一新平台为(1)提供了巨大的潜力 在相关患者样本上快速测试新的药物方案，从而加快PDAC药物的开发；以及 (2)提供个别化的药物筛选，为每个患者确定最有效和毒性最低的治疗方法。 这一提议将检验初级PDAC有机化合物的OMI可以准确地预测体内的假设 对小鼠和人类的治疗效果。此方法将在主PDAC的小鼠模型上进行验证 辅助治疗环境中的患者样本和转移治疗中的原始患者样本 布景。建议开发动态、单细胞评估技术来监测药物反应 完整的小鼠和人PDAC有机体中的多种细胞类型为合理药物提供了巨大的希望 开发和治疗计划，最终可以减少毒副作用并改善患者的预后。