PET Imaging-guided Personalized Therapy in Pancreatic Cancer

描述(申请人提供)：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)分析方法，用于患者分层，从而为PDAC提供更有效和更好的耐受性个性化治疗。吉西他滨(GEM)是PDAC中最常用的化疗药物，只有不到10%的患者观察到治疗反应。在已提出的GEM治疗PDAC疗效不佳的原因中，有两种机制被认为是主要的候选：(I)由于肿瘤相关间质血管和致密，GEM对PDAC肿瘤细胞的药物传递不佳，以及(Ii)PDAC肿瘤细胞对前药GEM的摄取和/或转化为其活性、细胞毒代谢产物的效率低下。为了支持前一种机制，新的间质耗竭(Sd)疗法，如Abraxane和聚乙二醇化透明质酸酶，改善了GEM对肿瘤细胞的输送，延长了临床前模型中的生存时间，对于Abraxane，在 病人。如果开发配套的诊断方法来衡量添加SD制剂是否增强了GEM在肿瘤细胞内的传递及其向治疗活性代谢物的转化，GEM可能会更有效地用于PDAC治疗。这项建议将检验如下假设，即加州大学洛杉矶分校研究人员开发的新的GEM类似PET探针1-L-(2-脱氧-2，-18氟-呋喃)胞嘧啶(18F-L-FAC)可用于确定(1)增加GEM向肿瘤细胞递送所需的SD制剂的最短时程；(2)PDAC患者瘤内GEM积聚和肿瘤细胞激活的效率。在目标1中，PET将用于在临床前模型中确定引起肿瘤探针(18F-L-FAC)和药物(GEM)释放可检测变化所需的最短间质耗竭治疗方案。目的2研究18F-L-FACPET测量SD治疗的PDAC患者肿瘤内宝石输送和代谢的准确性。预期的结果是一种新的PET检测，以确定哪些PDAC患者可能对联合应用GEM和SD疗法的PDAC患者有效。这项试验将解决目前胰腺癌治疗中尚未得到满足的临床需求，因为现在已经有了GEM/Abraxane的替代品，尽管对患者来说毒性要大得多，但现在已经有了替代方案。

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.