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: 8913913
• 负责人: JOHANNES CZERNIN
• 金额: $ 55.95万
• 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/8913913
• 关键词: Abraxane; Address; Biological Assay; Biological Markers; Blood Vessels; Clinical; Clinical Research; Companions; Cytosine; Deoxycytidine Kinase; Dose; Drug Delivery Systems; Excision; Face; Genetic Models; Health; Human; Hyaluronidase; 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; companion diagnostics; cytotoxic; gemcitabine; image guided; improved; liquid chromatography mass spectrometry; molecular imaging; neoplastic cell; oncology; personalized medicine; pre-clinical; 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（由申请人提供）：胰腺导管腺癌（PDAC）是一种恶性肿瘤，治疗结果令人沮丧。这项跨学科研究旨在为患者分层开发新的正电子发射断层扫描（PET）测定法，这可能会导致PDAC的更有效且耐受性更好的个性化疗法。在不到10％的患者中，观察到对PDAC中最常用的化学治疗剂的吉西他滨（GEM）的治疗反应。在PDAC中，PEM在PDAC中的次优疗效的提议原因中，有两个提出的机制已成为主要候选物：（i）由于血管性和密集的肿瘤相关的基质和（II）通过对Prodrug prodrug the prodox cytox cytox cytob cytob cytoctox的细胞，由于血管性肿瘤相关的基质和（ii）有效地摄入和/或对转换。为了支持以前的机制，新的基质耗竭（SD）疗法，例如Abraxane和pegypated透明质酸酶改善了GEM向肿瘤细胞的递送，在临床前模型中延伸了生存，并且在Abraxane，在Abraxane中，在In in Abraxane中， 患者。如果开发出伴随诊断剂来测量SD剂增强肿瘤内GEM的递送及其转化为肿瘤细胞的治疗活性代谢产物，则可以更有效地用于PDAC治疗。该提案将检验以下假设：UCLA研究人员开发的新的Gem Abalog PET探针1-l-（2-脱氧-2，-18fluoro-Arabinofuranosyl）胞嘧啶（18F-L-FAC）可用于确定（1）通过（1）确定（1）SD代理的最短时间表，以增加对肿瘤细胞和（2）gem interiation的最短时间表，并激发肿瘤细胞的extim效率（2）gem intivil效率（2）intivor效应，并激活了（2）gemor的效率（2） PDAC患者。在AIM 1中，将使用PET来确定临床前模型中最短的基质耗竭疗法时间表，以诱导肿瘤探针（18F-L-FAC）和药物（GEM）递送的可检测变化。 AIM 2提出的研究旨在确定通过SD疗法治疗的PDAC患者的18F-L-FAC PET测量肿瘤内宝石递送和代谢的准确性。预期的结果是一种新的宠物分析，可以识别可能与SD疗法结合使用的GEM的PDAC患者。该测定方法将解决胰腺癌管理中目前未满足的临床需求，因为现在可以使用Gem/Abraxane的替代品，尽管对患者的毒性更大。