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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.

项目总结/文摘