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.
| Qazi, Asif Khurshid; Siddiqui, Jawed A; Jahan, Rahat et al. (2018) Emerging therapeutic potential of graviola and its constituents in cancers. Carcinogenesis 39:522-533 |
| Tiriac, Hervé; Belleau, Pascal; Engle, Dannielle D et al. (2018) Organoid Profiling Identifies Common Responders to Chemotherapy in Pancreatic Cancer. Cancer Discov 8:1112-1129 |
| Qi, Bowen; Crawford, Ayrianne J; Wojtynek, Nicholas E et al. (2018) Indocyanine green loaded hyaluronan-derived nanoparticles for fluorescence-enhanced surgical imaging of pancreatic cancer. Nanomedicine 14:769-780 |
| Goodwin, Justin; Choi, Hyunsung; Hsieh, Meng-Hsiung et al. (2018) Targeting Hypoxia-Inducible Factor-1?/Pyruvate Dehydrogenase Kinase 1 Axis by Dichloroacetate Suppresses Bleomycin-induced Pulmonary Fibrosis. Am J Respir Cell Mol Biol 58:216-231 |
| Coelho, Sílvia Castro; Reis, Daniel Pires; Pereira, Maria Carmo et al. (2018) Gold Nanoparticles for Targeting Varlitinib to Human Pancreatic Cancer Cells. Pharmaceutics 10: |
| Krishn, Shiv Ram; Ganguly, Koelina; Kaur, Sukhwinder et al. (2018) Ramifications of secreted mucin MUC5AC in malignant journey: a holistic view. Carcinogenesis 39:633-651 |
| Cannon, Andrew; Thompson, Christopher; Hall, Bradley R et al. (2018) Desmoplasia in pancreatic ductal adenocarcinoma: insight into pathological function and therapeutic potential. Genes Cancer 9:78-86 |
| Nimmakayala, Rama Krishna; Seshacharyulu, Parthasarathy; Lakshmanan, Imayavaramban et al. (2018) Cigarette Smoke Induces Stem Cell Features of Pancreatic Cancer Cells via PAF1. Gastroenterology 155:892-908.e6 |
| Robb, Caroline M; Kour, Smit; Contreras, Jacob I et al. (2018) Characterization of CDK(5) inhibitor, 20-223 (aka CP668863) for colorectal cancer therapy. Oncotarget 9:5216-5232 |
| Attri, Kuldeep S; Mehla, Kamiya; Shukla, Surendra K et al. (2018) Microscale Gene Expression Analysis of Tumor-Associated Macrophages. Sci Rep 8:2408 |
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