Imaging drug uptake and distribution in chemoradiation therapy of pancreatic cancer

胰腺癌放化疗中的影像学药物摄取和分布

基本信息

批准号：
9185682
负责人：
JOHN L HUMM
金额：
$ 66.06万
依托单位：
SLOAN-KETTERING INST CAN RESEARCH
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-07-01 至 2020-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9185682
关键词：
Accounting Acids Aftercare American Association of Cancer Research Animals Antineoplastic Agents Autoradiography Biodistribution Biological Blood Vessels Cell Cycle Cell Hypoxia Cell Proliferation Cells Clinical Clinical Protocols Clinical Research Clinical Treatment Clinical Trials Computer Simulation Cytosine Data Deoxycytidine Dependence Diagnostic Distant Dose Drug Targeting Drug usage Effectiveness Engineering Esters Experimental Animal Model Experimental Neoplasms External Beam Radiation Therapy Goals Histology Human Hypoxia Image Imidazole Immunohistochemistry Implant In Situ Injection of therapeutic agent Isotopes Label Local Therapy Malignant Neoplasms Malignant neoplasm of pancreas Measurable Measures Methods Modeling Mus Nude Mice Pancreas Patients Pharmaceutical Preparations Population Positron-Emission Tomography Prodrugs Proliferating Protocols documentation Radiation Radiation therapy Randomized Regimen Research Project Grants Resectable Resistance System Techniques Testing Therapeutic Time Tissues Tracer Transgenic Organisms Treatment Efficacy Treatment Protocols Unresectable Work abstracting analog base chemoradiation clinically relevant cone-beam computed tomography design digital drug distribution gemcitabine imaging modality improved killings mathematical model models and simulation molecular imaging neoplastic cell non-invasive imaging novel nucleoside analog pancreatic neoplasm phase III trial pre-clinical preclinical study radiosensitizing radiotracer response simulation standard of care symposium treatment planning tumor tumor microenvironment uptake

项目摘要

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.

项目概要/摘要胰腺癌放化疗中的影像学药物摄取和分布该提案是一项临床前研究，旨在调查药物摄取和分布如何变化，当与放射治疗联合施用。实验性肿瘤模型将包括人类胰腺原位植入裸鼠体内的细胞系和转基因（KPC）模型被设计为自发产生组织学与人类癌症非常相似的胰腺癌。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。该提案有 3 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配通过14C标记的吉西他滨和TH-302药物的数字放射自显影；然后表征该分布使用免疫组织化学相对于药物靶点（增殖和缺氧细胞）。第二部分将验证 PET 成像示踪剂，可以对药物分布及其目标进行非侵入性成像。其中包括： (i) 核苷类似物 (8F-FAC)，可通过 PET 定量分析吉西他滨在体内的摄取情况胰腺肿瘤，(ii) 氟胸苷 (18F-FLT) 来量化增殖的肿瘤细胞，这是吉西他滨的靶标作用和 (iii) 氟米索硝唑 (18F-FMISO) 来量化肿瘤缺氧，这是 TH-302 的目标。具体目标 2 是一个治疗目标，将测量放疗对吉西他滨和 TH-302 的影响药物的摄取和分布，以及改变摄取和再分布的治疗后果。二将研究放射治疗方案：(i) 6.6 Gy 的 5 次剂量和 (ii) 15 Gy 的单次高剂量剂量。放射治疗将使用专用的小动物照射器进行，并在上生成治疗计划适合委托的 X 射线束轮廓的临床系统。这种方法允许交付原位和转基因小鼠胰腺肿瘤的适形辐射，由一种新的逆定义对比锥束CT方法有利于准确模拟临床放化疗方案。具体目标 3 将纳入 SA1 和治疗药物摄取变化的测量数据 SA2 的这些变化的影响转化为数学模型，该模型模拟肿瘤细胞对药物与放射治疗相结合。放射、吉西他滨和 TH-302 的相对有效性均取决于肿瘤微环境以及增殖和缺氧克隆原比例的变化。模型将进行模拟来估计最佳放化疗方案。这些将被测试我们的临床前实验动物模型，如果成功，将作为设计的基本原理胰腺癌患者的临床方案。