The overall goal of this project is to develop telomere and telomerase interactive agents that improve the survival and quality of life of patients with cancer. Telomeres are repetitive sequences (TTAGGG in humans) at the ends of chromosomes, which have been called """"""""chemical bookends."""""""" The integrity of telomeres is vital for cell survival. As cells divide (age), the length of telomeres gradually decreases which leads to chromosome instability. When telomeres become very short, cells undergo a crisis. The cells that survive are immortal and have an increase in the enzyme telomerase. Telomerase is a reverse transcriptase that synthesizes and maintains telomeres. Important to this application are two facts: l) tumor cells have shorter telomeres than do normal cells (because the tumor cells have undergone more divisions); and 2) telomerase is produced in tumor cells (and not in normal cells). These two facts give us unique targets which are different in tumor cells versus normal cells and provide an opportunity to develop agents that affect tumor cells but not normal cells (good selectivity). We have assembled a group experienced in preclinical and clinical drug development who will tackle these targets using four programs and three cores. Program #1 (""""""""Characterization of Telomerase and Its Inhibitors"""""""") will purify telomerase and begin to elucidate the mechanism of action and the structure-activity relationship for inhibitors of telomerase that we have already identified. Program #2 (""""""""Rational Design and Synthesis of Telomerase Inhibitors"""""""") will utilize high-field NMR to elucidate unique targets within telomeres and telomerase and use molecular modeling to design drugs that will interact specifically with telomerase. Program #3 (""""""""Telomere and Telomerase Molecular Biology"""""""") will both map and clone telomere protein components and isolate and clone telomerase template RNA. These efforts will sharpen our understanding of the enzyme and its template RNA and provide us with even more specific targets. Program #4 (""""""""Telomeres and Telomerase in Primary and Metastatic Human Tumors"""""""") will characterize telomere length and telomerase levels in tumors taken directly from patients with breast, lung, head and neck, colon and ovarian cancer. This should identify patient malignancies that can be targeted in future clinical trials with agents developed via this project. In addition, clinically relevant animal model systems will be developed for in vivo testing of our candidate compounds. Finally, there will be three cores including l) an Administrative Core (""""""""A"""""""") for coordinating the efforts among our three institutions as well as with the NCI, 2) a Chemistry Core (""""""""B"""""""") for compound synthesis and analytical work, and 3) a Biology Core (""""""""C"""""""") for running assays to determine cell viability, in vitro telomerase level, and telomere length. We are confident that this approach to the design and synthesis of telomere/telomerase interactive agents will lead to agents that improve the survival and quality of life of patients with cancer.
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