Telomerase activity has been found in most types of human tumors, but not in adjacent normal cells. This correlation has led to the hypothesis that reactivation of telomerase is necessary for the sustained proliferation that characterizes cancer, and that telomerase is a novel target for chemotherapy. The validity of this hypothesis has been vigorously debated, and effective inhibitors of telomerase are needed to understand how blocking telomerase activity will affect cancer cell phenotypes and proliferation. To discover the potential for telomerase as a target for chemotherapy Dr. Corey is developing oligonucleotides and oligonucleotide mimics as highly selective and potent inhibitors. These oligomers are well suited to achieving unambiguous insights into the consequences of telomerase inhibition because they take advantage of the potential for stringently selective recognition inherent in Watson-Crick base-pairing. An oligomer complementary to a target sequence should exert a sequence-specific physiologic effect, whereas the mismatch containing oligomer should not. They now propose to continue to develop synthetic telomerase inhibitors, characterize the effects of telomerase inhibition on the proliferation of varied lines of cultured cells, and perform preclinical studies in mouse models of human cancer. This research will be integrated into a cycle of experiments in which the observed effects of inhibitors in cell culture and animals will rapidly lead to revised inhibitor designs and renewed testing for efficacy. These studies will characterize the in vivo effects of inhibitors of telomerase, permit investigation of the side effects of antitelomerase therapy, and provide insights that will be generally applicable to the development of all classes of telomerase inhibitors.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
1R01CA085363-01A1
Application #
6258512
Study Section
Cell Development and Function Integrated Review Group (CDF)
Program Officer
Forry, Suzanne L
Project Start
2001-02-08
Project End
2005-01-31
Budget Start
2001-02-08
Budget End
2002-01-31
Support Year
1
Fiscal Year
2001
Total Cost
$351,000
Indirect Cost
Name
University of Texas Sw Medical Center Dallas
Department
Pharmacology
Type
Schools of Medicine
DUNS #
City
Dallas
State
TX
Country
United States
Zip Code
75390
Li, Yingming; Malaeb, Bahaa S; Li, Zhong-Ze et al. (2010) Telomerase enzyme inhibition (TEI) and cytolytic therapy in the management of androgen independent osseous metastatic prostate cancer. Prostate 70:616-29
Huffman, Kenneth E; Corey, David R (2005) Major vault protein does not play a role in chemoresistance or drug localization in a non-small cell lung cancer cell line. Biochemistry 44:2253-61
Takakura, Masahiro; Kyo, Satoru; Inoue, Masaki et al. (2005) Function of AP-1 in transcription of the telomerase reverse transcriptase gene (TERT) in human and mouse cells. Mol Cell Biol 25:8037-43
Natarajan, Shobhana; Chen, Zhi; Wancewicz, Edward V et al. (2004) Telomerase reverse transcriptase (hTERT) mRNA and telomerase RNA (hTR) as targets for downregulation of telomerase activity. Oligonucleotides 14:263-73
Kaihatsu, Kunihiro; Huffman, Kenneth E; Corey, David R (2004) Intracellular uptake and inhibition of gene expression by PNAs and PNA-peptide conjugates. Biochemistry 43:14340-7
Paroo, Zain; Bollinger, Robert A; Braasch, Dwaine A et al. (2004) Validating bioluminescence imaging as a high-throughput, quantitative modality for assessing tumor burden. Mol Imaging 3:117-24
Paroo, Zain; Corey, David R (2003) Imaging gene expression using oligonucleotides and peptide nucleic acids. J Cell Biochem 90:437-42
Chen, Zhi; Corey, David R (2003) Telomerase inhibitors: a new option for chemotherapy. Adv Cancer Res 87:31-58
Barma, D K; Elayadi, Anissa; Falck, J R et al. (2003) Inhibition of telomerase by BIBR 1532 and related analogues. Bioorg Med Chem Lett 13:1333-6
Chen, Zhi; Koeneman, Kenneth S; Corey, David R (2003) Consequences of telomerase inhibition and combination treatments for the proliferation of cancer cells. Cancer Res 63:5917-25

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