PET Imaging-guided Personalized Therapy in Pancreatic Cancer

PET 成像引导的胰腺癌个性化治疗

• 批准号: 8750786
• 负责人: JOHANNES CZERNIN
• 金额: $ 51.86万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-08-18 至 2019-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8750786
• 关键词: Abraxane; Address; Biological Assay; Biological Markers; Blood Vessels; Clinical; Clinical Research; Companions; Cytosine; Deoxycytidine Kinase; Diagnostic; Dose; Drug Delivery Systems; Excision; Face; Genetic Models; Human; Hyaluronidase; Image; Interdisciplinary Study; Lead; Left; Liquid Chromatography; Malignant Neoplasms; Malignant neoplasm of pancreas; Mass Spectrum Analysis; Measures; Metabolism; Modeling; Mus; Oncologist; Operative Surgical Procedures; Outcome; Pancreatic Ductal Adenocarcinoma; Patients; Perfusion; Pharmaceutical Preparations; Positron-Emission Tomography; Pre-Clinical Model; Prodrugs; Proteins; Regimen; Research Personnel; Resected; Scanning; Schedule; Stratification; Survival Rate; Testing; Therapeutic; Time; Translational Research; Tumor Tissue; Xenograft procedure; analog; cancer therapy; chemotherapeutic agent; cytotoxic; gemcitabine; improved; liquid chromatography mass spectrometry; molecular imaging; neoplastic cell; oncology; pre-clinical; public health relevance; resistance mechanism; response; tandem mass spectrometry; tumor; uptake

DESCRIPTION (provided by applicant): Pancreatic ductal adenocarcinoma (PDAC) is a malignancy with a dismal therapeutic outcome. This interdisciplinary study aims to develop a new Positron Emission Tomography (PET) assay for patient stratification, which could lead to more efficacious and better tolerated personalized therapies for PDAC. Therapeutic responses to gemcitabine (GEM), the most frequently used chemotherapeutic agent in PDAC, are observed in less than 10% of patients. Amongst proposed reasons for GEM's suboptimal efficacy in PDAC two suggested mechanisms have emerged as leading candidates: (i) suboptimal drug delivery to PDAC tumor cells because of a poorly vascularized and dense tumor-associated stroma and (ii) inefficient uptake and/or conversion of the prodrug GEM to its active, cytotoxic metabolites by the PDAC tumor cells. In support of the former mechanism, new stromal depleting (SD) therapies, such as Abraxane and pegylated hyaluronidase improve GEM delivery to tumor cells, extending survival in preclinical models, and, in the case of Abraxane, in patients. GEM could be used more effectively for PDAC therapy if companion diagnostics are developed to measure if the addition of a SD agent enhances intratumoral GEM delivery and its conversion to therapeutically active metabolites in tumor cells. This proposal will test the hypothesis that a new GEM analog PET probe 1-L-(2-Deoxy-2,-18Fluoro-Arabinofuranosyl) Cytosine (18F-L-FAC) developed by UCLA investigators can be used to determine (1) the shortest schedule of SD agents required to increase GEM delivery to tumor cells, and (2) the efficiency both of intratumoral GEM accumulation and activation by tumor cells in PDAC patients. In Aim 1, PET will be used to determine, in preclinical models, the shortest schedule of stromal depleting therapy required to induce detectable changes in tumor probe (18F-L-FAC) and drug (GEM) delivery. Aim 2 proposes study to determine the accuracy of 18F-L-FAC PET measures of intra-tumoral GEM delivery and metabolism in PDAC patients treated with SD therapies. The expected outcome is a new PET assay to identify PDAC patients who are likely responders to GEM administered in combination with SD therapies. This assay will address a currently unmet clinical need in pancreatic cancer management since alternatives to GEM/Abraxane, albeit considerably more toxic for patients, are now available.

描述（由申请方提供）：胰腺导管腺癌（PDAC）是一种治疗结果令人沮丧的恶性肿瘤。这项跨学科研究旨在开发一种新的正电子发射断层扫描（PET）检测方法，用于患者分层，这可能导致PDAC更有效，耐受性更好的个性化治疗。吉西他滨（GEM）是PDAC中最常用的化疗药物，在不到10%的患者中观察到治疗反应。在提出的GEM在PDAC中的次优功效的原因中，两种建议的机制已经作为主要候选者出现：（i）由于血管化不良和致密的肿瘤相关基质，次优的药物递送至PDAC肿瘤细胞和（ii）前药GEM被PDAC肿瘤细胞低效摄取和/或转化为其活性细胞毒性代谢物。为了支持前一种机制，新的基质消耗（SD）疗法，如Abraxane和聚乙二醇化透明质酸酶，改善了GEM向肿瘤细胞的递送，延长了临床前模型中的存活期，并且在Abraxane的情况下，改善了肿瘤细胞的存活率。 患者如果开发伴随诊断以测量添加SD剂是否增强肿瘤内GEM递送及其在肿瘤细胞中向治疗活性代谢物的转化，则GEM可更有效地用于PDAC治疗。该提案将检验由UCLA研究者开发的新的GEM类似物PET探针1-L-（2-脱氧-2，18-氟-阿拉伯呋喃糖基）胞嘧啶（18 F-L-FAC）可用于确定（1）增加GEM递送至肿瘤细胞所需的SD剂的最短时间表，以及（2）PDAC患者中肿瘤细胞的肿瘤内GEM积累和激活的效率的假设。在目标1中，PET将用于在临床前模型中确定诱导肿瘤探针（18 F-L-FAC）和药物（GEM）递送的可检测变化所需的基质消耗治疗的最短时间表。目的2提出了一项研究，以确定18 F-L-FAC PET测量接受SD治疗的PDAC患者肿瘤内GEM递送和代谢的准确性。预期的结果是一种新的PET测定，以识别可能对GEM联合SD治疗有反应的PDAC患者。该测定将解决胰腺癌管理中目前未满足的临床需求，因为目前已有GEM/Abraxane的替代品，尽管对患者的毒性更大。