Mechanistic and Translational Studies of PR-104:A New Hypoxia Activated Cytotoxin

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The goal of this project is to perform mechanistic and translational studies with a new and highly effective hypoxia-activated drug, PR-104, particularly in evaluating its potential for combination with radiotherapy and with gemcitabine. PR-104 is a dinitrobenzamide mustards (DNBM), recently discovered by our collaborators Drs. Denny and Wilson, with improved properties over the current prototype of a hypoxic cytotoxin, tirapazamine (TPZ), including a substantial bystander killing that gives it activity against aerobic as well as hypoxic cells in solid tumors. It entered Phase 1 clinical trials in January 2006. The benefit of combining a hypoxic cytotoxin with conventional anticancer therapy is based on the fact that most human solid tumors have regions at low oxygen levels (hypoxia) and the cells in these regions are resistant to killing by radiation and many chemotherapeutic drugs. TPZ has already demonstrated clinical benefit in combination with radiotherapy and cisplatin based chemotherapy. Our preliminary studies show that PR-104 is superior to TPZ in combination with fractionated radiation with two different human tumor xenografts as well as having substantial single agent activity. We will focus on head and neck and pancreatic cancers, the former with fractionated radiation and the latter with gemcitabine. The tumor efficacy studies with radiation will be performed with different human head and neck tumor xenografts with PR-104 in parallel with TPZ in order to compare their relative efficacies, and the studies with PR-104 in combination with gemcitabine will be performed with pancreatic xenografts both as subcutaneous and orthotopic models. Our specific aims are 1) to compare the efficacy of PR-104 and TPZ in potentiating fractioned irradiation to head and neck xenografts, 2) to measure the distribution of active PR-104 metabolites in tumors by assaying DMA interstrand crosslinks by the alkaline comet assay 3) to assay the efficacy and mechanism of action of PR- 104 in combination with gemcitabine with pancreatic tumor xenografts, 4) to determine the extent to which the activity of PR-104 with or without irradiation can be increased by increasing tumor hypoxia using vascular targeting agents 5) to determine the extent to which the activity of PR-104 can be increased using NTR expressing C.sporogenes, and 6) to test the hypothesis that the Gl toxicity of PR-104 can be reduced by reduction of intestinal microflora. This project has direct applicability to human health: It's rationale is the same as that of TPZ, the first hypoxic cytotoxin to show clinical benefit, yet PR-104 appears to be superior to TPZ, and therefore has the potential of improving cancer cure rates to a greater extent than does TPZ