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.
This project proposes imaging methods to determine the uptake in mice with pancreatic cancer of two complementary anti-cancer drugs: (i) gemcitabine, which kills rapidly dividing tumor cells and (ii) TH-302, which kills resistant tumor cells that hide in so-called ?hypoxic? regions distant from blood vessels and therefore difficult for drugs to reach. It will investigate the effect of radiotherapy on the uptake of these drugs and determine how to combine them in an optimum way to maximize the therapeutic impact. The clinical implications of the successful use of non-invasive molecular imaging to optimize concurrent therapy are significant, given the current lack of effective local therapy options for patients with unresectable pancreatic cancer.
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