Imaging drug uptake and distribution in chemoradiation therapy of pancreatic cancer
Imaging drug uptake and distribution in chemoradiation therapy of pancreatic cancer
批准号:
9185682
负责人:
JOHN L HUMM
金额:
$66.06万
依托单位国家:
美国
项目类别:
财政年份:
2016
资助国家:
美国
项目状态:
已结题
起止时间:
2016-07-01 至 2020-06-30
关键词:
AccountingAcidsAftercareAmerican Association of Cancer ResearchAnimalsAntineoplastic AgentsAutoradiographyBiodistributionBiologicalBlood VesselsCell CycleCell HypoxiaCell ProliferationCellsClinicalClinical ProtocolsClinical ResearchClinical TreatmentClinical TrialsComputer SimulationCytosineDataDeoxycytidineDependenceDiagnosticDistantDoseDrug TargetingDrug usageEffectivenessEngineeringEstersExperimental Animal ModelExperimental NeoplasmsExternal Beam Radiation TherapyGoalsHistologyHumanHypoxiaImageImidazoleImmunohistochemistryImplantIn SituInjection of therapeutic agentIsotopesLabelLocal TherapyMalignant NeoplasmsMalignant neoplasm of pancreasMeasurableMeasuresMethodsModelingMusNude MicePancreasPatientsPharmaceutical PreparationsPopulationPositron-Emission TomographyProdrugsProliferatingProtocols documentationRadiationRadiation therapyRandomizedRegimenResearch Project GrantsResectableResistanceSystemTechniquesTestingTherapeuticTimeTissuesTracerTransgenic OrganismsTreatment EfficacyTreatment ProtocolsUnresectableWorkabstractinganalogbasechemoradiationclinically relevantcone-beam computed tomographydesigndigitaldrug distributiongemcitabineimaging modalityimprovedkillingsmathematical modelmodels and simulationmolecular imagingneoplastic cellnon-invasive imagingnovelnucleoside analogpancreatic neoplasmphase III trialpre-clinicalpreclinical studyradiosensitizingradiotracerresponsesimulationstandard of caresymposiumtreatment planningtumortumor microenvironmentuptake
中文摘要
项目总结/文摘
英文摘要
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.
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