Imaging drug uptake and distribution in chemoradiation therapy of pancreatic cancer

项目总结/摘要 胰腺癌放化疗中药物摄取和分布的影像学研究 该提案是一项临床前研究，旨在研究药物摄取和分布的变化，当 与放射治疗联合施用。实验肿瘤模型将包括人胰腺癌。 原位植入裸鼠的细胞系和自发工程化的转基因（KPC）模型， 产生组织学与人类癌症非常相似的胰腺癌。该研究将重点 两种补充药物：（i）核苷类似物吉西他滨，管理中的标准护理 胰腺癌，它选择性地灭活增殖细胞和（ii）实验性缺氧激活 前药TH-302。该提案有三个具体目标。 具体目标1诊断目标由两部分组成。第一部分将确定吸收和分布 通过14 C-标记吉西他滨和TH-302药物的数字放射自显影;然后表征分布 相对于药物靶点（增殖和缺氧细胞），使用免疫组织化学。第二部分将 验证PET成像示踪剂，允许药物分布及其靶点的非侵入性成像。 这些包括：（i）核苷类似物（8 F-FAC），以允许PET定量吉西他滨的摄取， 胰腺肿瘤，（ii）氟胸苷（18 F-FLT），用于定量增殖的肿瘤细胞，吉西他滨的靶点 作用和（iii）氟咪唑（18F-FMISO）定量肿瘤缺氧，TH-302的目标。 特异性目标2是一个治疗目标，将测量放疗对吉西他滨和TH-302的影响 药物摄取和分布，以及改变的摄取和再分布的治疗分支。两 将研究放射治疗方案：（i）6. 6戈伊的5次分割和（ii）15戈伊的单次高剂量分割。 放射治疗将使用专用的小动物辐照器进行，并在 适用于委托的X射线射束轮廓的临床系统。这种方法允许交付 原位和转基因小鼠胰腺肿瘤的适形放射治疗，由一种新的逆转 对比锥形束CT方法，有助于准确模拟临床放化疗方案。 具体目标3将纳入关于来自SA 1和治疗药物的药物摄取变化的测量数据。 将这些变化从SA 2转化为数学模型，该模型模拟肿瘤细胞对 药物与放疗的结合。放疗、吉西他滨和TH-302的相对有效性都取决于 对肿瘤微环境以及增殖和缺氧克隆原的比例变化的影响。模型 将进行模拟以估计最佳化放疗方案。这些将在 我们的临床前实验动物模型，如果成功的话，将作为设计的基本原理， 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.