Telomeres progressively shorten in almost all normal human tissues with increased age. In preneoplasia, telomeres are exceptionally short. Almost all human malignant tumors express telomerase to maintain these short telomeres. This activity is absent or is at lower levels in normal tissues. This has led to approaches for inhibiting telomerase as a target for cancer therapeutics. Cancer stem cells have been shown to be both telomerase expressing and containing short telomeres. This suggests that telomerase inhibitors are likely to target both the bulk of the more differentiated tumor cells as well as the stem cells that provide the unlimited growth of most advanced cancers. This project will conduct pre-clinical orthotopic xenograft animal experiments followed by clinical trials in patients with pancreatic cancer. The preclinical experiments will evaluate the in vivo effectiveness of a novel telomerase inhibitor just entering clinical trials, GRN163L, on human pancreatic cancer cells in mice bearing orthotopic tumors in the pancreas. GRN163L has enhanced stability and displays extremely specific and high-affinity binding to telomerase. These properties increase the chances of effectively inhibiting telomerase in cancer cells throughout the body with relatively low doses of the drug. We have already demonstrated that our lead compound, GRN163L, is an effective inhibitor of telomerase in several types of cancer cell lines. The proposed experiments will use bioluminescence imaging to follow human pancreatic tumor cell lines treated in vivo with GRN163L alone and in combination with chemotherapy. The goal is to monitor the spatio-temporal distribution of pancreatic tumor cells during the disease course from minimal residual disease to metastasis with and without GRN163L and combinations of chemotherapy. The experiments should unambiguously prove or disprove the link between the inhibition of telomerase and decreased proliferation of tumor cells in vivo. In this proposal, we will exploit this knowledge to conduct early stage clinical trials on pancreatic cancer patients with locally advanced, unresectable, or metastatic disease. For these patients, a standard treatment option is the combination of gemcitabine with erlotinib (www.nccn.org). In a phase l/ll trial, prolonged exposure to GRN163L will be administered in combination with gemcitabine/erlotinib chemotherapy, and the safety and efficacy of GRN163L will be determined. The primary endpoints will be telomerase inhibition, survival and progression-free survival. From a subset of patients, pancreatic juice will be obtained to measure the impact of GRN163L on telomerase activity at the tumor site. From patients that agree to participate in an ongoing rapid autopsy program, measurements of telomere size in tumors will also be obtained at time of death. This trial is likely to the first clinical trials testing a telomerase inhibitor in patients with pancreatic cancer.
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