Innovative Approaches

Telomeres

In the human body, normal growth and maintenance of tissues occurs by cell division. However, most cells in the body are only able to divide a limited number of times, and this is regulated by telomeres. Telomeres are repeats of the DNA sequence TTAGGG and associated proteins located at the ends of chromosomes. Telomeres act as protective caps to maintain stability and integrity of the chromosomes, which contain the cell’s genetic material. Every time a cell replicates the telomeres shorten; eventually, when they shrink to a certain length, the cell either dies by apoptosis or stops dividing and senesces.

Telomerase

Telomerase is an enzyme that can rebuild telomeres and prevent them from shortening during cell division. Telomerase consists of at least two essential components: the RNA template (hTR), which binds to the telomere, and the catalytic subunit (hTERT) with reverse transcriptase activity, which adds the specific DNA sequence to the chromosome ends. In addition to telomere maintenance, telomerase acts through other mechanisms that contribute to increased cell proliferation.

Telomerase is active during embryonic development when cells are rapidly dividing to support normal growth. During the latter stages of human fetal development, telomerase activity is completely repressed in most somatic cells and is downregulated in tissue stem cells. These tissue stem cells, such as hematopoietic stem cells in the bone marrow, express telomerase periodically during periods of cell proliferation. Most normal adult cells do not have detectable telomerase activity and telomere length gradually decreases throughout life.

Telomerase and Cancer

When a cell is transformed to become a cancer cell, it divides frequently and the telomeres become very short compared to normal cells. To maintain critically short telomeres and prevent cell death, tumor cells reactivate telomerase. The activation of telomerase itself does not cause a normal cell to become malignant, but is necessary for cancer cells to proliferate without limit, becoming essentially immortal. Telomerase has been found to be present in approximately 90% of biopsies from a broad range of human cancers and activity is generally found to increase with grade and stage of tumor.

Telomerase is a key molecular target in oncology today. Inhibiting or blocking the activity of telomerase may be an important approach to targeting cancer, and one that may be broadly applicable in a wide variety of tumor types. Because telomerase is active in cancer cells, but not, or rarely, active in normal cells, and the telomeres of chromosomes are shorter in tumor cells compared to normal cells, telomerase inhibition may be less toxic to normal cells than conventional chemotherapy agents and non-targeted anti-cancer therapies.

Targeting Telomerase in Cancer

Geron is exploring multiple approaches to targeting telomerase in cancer. Geron is developing a telomerase inhibitor, imetelstat, as a potential anti-cancer therapy, which is currently in clinical development for the treatment of solid tumors and hematological malignancies. Imetelstat was the first, and is the only telomerase inhibitor drug in clinical development today.

Activating Telomerase in Disease

While telomerase is a target for novel anti-cancer therapies, early experiments also showed that by introducing telomerase into normal cells in culture, their replicative potential was increased without malignant transformation. Controlled activation of telomerase may restore the regenerative or functional capacity of cells no longer capable of replication in various organ systems that are impacted by senescence, injury or chronic disease. Geron scientists and collaborators are investigating the potential therapeutic application of small molecule telomerase activators using model systems of human disease.