Imaging drug uptake and distribution in chemoradiation therapy of pancreatic cancer

项目摘要/摘要 胰腺癌放化疗中显像剂的摄取与分布 这项建议是一项临床前研究，旨在调查药物摄取和分布的变化，当 与放射治疗一起使用。实验性肿瘤模型将包括人胰腺 裸鼠原位移植细胞系和转基因(KPC)模型 导致胰腺癌，其组织结构与人类癌症非常相似。这项研究将集中于 关于两种相辅相成的药物：(一)核苷类似物吉西他滨，管理中的护理标准 胰腺癌，选择性地灭活增殖细胞和(Ii)实验性缺氧激活 前药TH-302。这项建议有三个具体目标。 具体目标1由两部分组成的诊断目标。第一部分将确定吸收和分配 通过~(14)C标记的吉西他滨和TH-302药物的数字放射自显影；然后描述其分布 与药物靶点(增殖和低氧细胞)相关的免疫组织化学。第二部分将 验证PET成像示踪剂，允许对药物分布及其靶点进行非侵入性成像。 其中包括：(I)核苷类似物(8F-FAC)，以允许PET定量测定吉西他滨在体内的摄取 胰腺肿瘤，(Ii)氟胸腺苷(18F-Flt)，用于量化肿瘤细胞的增殖，吉西他滨的靶点 作用和(Iii)氟咪唑(18F-FMISO)以量化肿瘤缺氧，TH-302的靶点。 具体目标2是一个治疗目标，将衡量放射治疗对吉西他滨和TH-302的影响 药物摄取和分配，以及改变摄取和重新分配的治疗后果。二 将研究放射治疗方案：(I)5次6.6Gy5次，和(Ii)15Gy单次高剂量次。 放射治疗将使用专门的小动物辐照器进行，治疗计划将在 一种适用于委托使用的X射线束轮廓的临床系统。此方法允许交付 用一种新的逆法定义适形放射治疗原位和转基因小鼠胰腺肿瘤 对比锥束CT方法有助于准确模拟临床放化疗方案。 具体目标3将纳入SA1和治疗性药物摄取变化的测量数据 从SA2到数学模型的这些变化的影响，该数学模型模拟肿瘤细胞对 与辐射相结合的药物。辐射、吉西他滨和TH-302的相对有效性都取决于 肿瘤微环境以及增殖和低氧克隆细胞比例的变化。型号 将进行模拟以评估最佳的放化疗方案。这些将在 我们的临床前实验动物模型，如果成功，将作为设计 胰腺癌患者的临床方案。

Project Summary/Abstract Imaging drug uptake and distribution in chemoradiation therapy of pancreatic cancer This proposal is a preclinical study to investigate how drug uptake and distribution changes, when administered in conjunction with radiation therapy. Experimental tumor models will include human pancreatic lines orthotopically implanted into nude mice and transgenic (KPC) models engineered to spontaneously generate pancreatic cancer with histologies that closely resemble those of human cancers. The study will focus on two complementary drugs: (i) the nucleoside analog gemcitabine, the standard of care in the management of pancreatic cancer, which selectively inactivates proliferating cells and (ii) an experimental hypoxia-activated prodrug TH-302. There are 3 specific aims in this proposal. Specific Aim 1 a diagnostic aim consisting of two parts. The first part will determine the uptake and distribution by digital autoradiography of 14C-labeled gemcitabine and TH-302 drug; then characterize that distribution relative to drug targets (proliferating and hypoxic cells) using immunohistochemistry. The second part will validate PET imaging tracers that would allow non-invasive imaging of the drug distribution and their targets. These include: (i) a nucleoside analog (8F-FAC) to allow PET quantification of the uptake of gemcitabine in pancreatic tumors, (ii) fluorothymidine (18F-FLT) to quantify proliferating tumor cells, the targets for gemcitabine action and (iii) fluoromisonidazole (18F-FMISO) to quantify tumor hypoxia, the target for TH-302. Specific Aim 2 is a therapeutic aim that will measure the effects of radiotherapy on gemcitabine and TH-302 drug uptake and distribution, and the therapeutic ramifications of altered uptake and redistribution. Two radiotherapy protocols will be studied: (i) 5 fractions at 6.6 Gy and (ii) a single high-dose fraction of 15 Gy. Radiation therapy will be delivered using a dedicated small animal irradiator with treatment plans generated on a clinical system adapted for the commissioned x-ray beam profiles. This approach allows the delivery of conformal radiation to orthotopic and transgenic murine pancreatic tumors in-situ, defined by a novel inverse contrast cone-beam CT method facilitating accurate simulation of clinical chemoradiation therapy regimens. Specific aim 3 will incorporate the measured data on drug uptake changes from SA1 and the therapeutic impact of those changes from SA2 into a mathematical model, which simulates the tumor cell response to drugs in combination with radiation. The relative effectiveness of radiation, gemcitabine and TH-302 all depend upon the tumor microenvironment and the changing proportion of proliferating and hypoxic clonogens. Model simulations will be performed to estimate the optimum chemoradiotherapy protocols. These will be tested on our pre-clinical experimental animal models, which, if successful, will serve as a rationale for the design of clinical protocols in patients with pancreatic cancer.