Telomeres and Telomerase in Cancer Development 20 March 2008 Hannah Yin (

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)

DNA End Replication and Telomere Shortening (Wikipedia.com) (universe-review.ca)

Telomerase Structure and Function heterotetramer hTERC: RNA template portion hTERT: DNA polymerase enzymatic portion Reverse transcriptase (Hahn, 2003)

Telomeres and Telomerase in 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 Hayflick Limit (Amazon.com)

IMMORTALIZATION Cells must… Overcome replicative senescence AND Escape regulation of the cell cycle

Telomerase activity is NECESSARY…

…but NOT SUFFICIENT

The Path to Immortality (Hahn, 2003)

Paradigm: Telomerase and Cancer (Hahn, 2003)

What happens if we Knock Out Telomerase?

(Blasco, et al, 1997)

Diagnostics (Eiso Hiyama & Keiko Hiyama, 2002)

Therapeutics – Small molecule inhibitors of telomerase reverse transcriptase RTIs already exist for treatment of HIV! – Specific inhibitors that target the active site of telomerase BIBR1532, 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)

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??

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) (