Telomeres and Telomerase

in Cancer Development

20 March 2008Hannah Yin

(www.biovita.fi)

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 Replicationand Telomere Shortening

(Wikipedia.com)(universe-review.ca)

Telomerase Structure and Function

heterotetramer

hTERC: RNA template portionhTERT: DNA polymerase enzymatic portion

Reverse transcriptase

(Hahn, 2003)

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)

IMMORTALIZATION

Cells must…Overcome replicative senescence

ANDEscape regulation of the cell cycle

Telomerase activity is NECESSARY…

…butNOT

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 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)

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)(www.lbl.gov)