Telomeres and Telomerase in Cancer Development 20 March 2008 Hannah Yin ()
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Transcript of Telomeres and Telomerase in Cancer Development 20 March 2008 Hannah Yin ()
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Telomeres and Telomerase
in Cancer Development
20 March 2008Hannah Yin
(www.biovita.fi)
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Telomere Structure and Function
Specialized chromosomal terminal structures – caps that guard the chromosome from recognition as a product of DNA fragmentation
Regulate chromosomal integrity and cell life span (Hahn, 2003)
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DNA End Replicationand Telomere Shortening
(Wikipedia.com)(universe-review.ca)
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Telomerase Structure and Function
heterotetramer
hTERC: RNA template portionhTERT: DNA polymerase enzymatic portion
Reverse transcriptase
(Hahn, 2003)
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Telomeres and Telomerasein Normal vs. Immortal Cells
In normal presenescent human cells- Telomerase activity is repressed- Telomeres shorten with successive cell
divisions- Limited proliferative capacity in culture
In cancer cell lines- Telomerase activity maintains stable telomere lengths- Unlimited replicative potential
HayflickLimit
(Amazon.com)
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IMMORTALIZATION
Cells must…Overcome replicative senescence
ANDEscape regulation of the cell cycle
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Telomerase activity is NECESSARY…
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…butNOT
SUFFICIENT
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The Path to Immortality
(Hahn, 2003)
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Paradigm: Telomerase and Cancer
(Hahn, 2003)
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What happens if we Knock Out Telomerase?
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(Blasco, et al, 1997)
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Diagnostics
(Eiso Hiyama & Keiko Hiyama, 2002)
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Therapeutics– Small molecule inhibitors of telomerase reverse transcriptase
RTIs already exist for treatment of HIV!
– Specific inhibitors that target the active site of telomeraseBIBR1532, a synthetic, non-nucleosidic drug
(Pascolo et al, 2002)
– Cellular immunotherapy“Data from both human and murine systems
demonstrate that cytotoxic T-lymphocytes (CTL) can recognize peptides derived from TERT and kill TERT-positive tumor cells of multiple histologies. Given the vast overexpression of hTERT in human tumors and its low-level expression in rare normal tissues, clinical trials have begun that test the credentials of hTERT as a broadly applicable target for immunotherapy of cancer.”
(Vonderheide, 2002)
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Considerations• Telomere lengths vary widely among different cancer cells,
and the mechanisms that control the length of telomeres in cancer cells are not yet understood
• Selection of non-telomerase-based mechanisms of telomere maintenance after prolonged treatment with telomerase inhibitors (evidence of ALT pathways)
• Some normal cells, including those with stem cell-like properties, retain the ability to activate telomerase physiologically side effects of long-term treatment with telomerase inhibitor or immunotherapy??
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Big Picture“Increasing our understanding of telomere
biology will not only identify targets for drug development but will also aid the efficient design of clinical trials to identify effective anti-telomere- and antitelomerase-based therapies.” (Hahn, 2003)
(GeneticsAndHealth.com)(www.lbl.gov)