PET Imaging-guided Personalized Therapy in Pancreatic Cancer

描述（由申请人提供）：胰腺导管腺癌（PDAC）是一种治疗效果不佳的恶性肿瘤。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，这可能会导致更有效和更耐受的PDAC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GEM对PDAC疗效欠佳的原因中，有两种可能的机制被认为是主要的候选机制：(i)由于PDAC肿瘤细胞血管化不良和致密的肿瘤相关基质，导致PDAC肿瘤细胞的药物递送不佳；（ii） PDAC肿瘤细胞对前药GEM的吸收和/或转化为活性的细胞毒性代谢物效率低下。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生存期

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.