Telomerase: Scientific Rationale

Nobel Prize Winning Science

Cell division plays a critical role in the normal growth, maintenance and repair of human tissue. Telomeres are repeated sequences of DNA at the ends of each chromosome, and are key genetic elements involved with the regulation of cell division. Telomeres shorten every time a cell divides, and once telomeres reach a critically short length, the cell either dies by apoptosis or stops dividing and senesces.

Telomerase is a naturally occurring enzyme that maintains telomeres and prevents them from shortening during cell division. Telomerase consists of at least two essential components: an RNA template, which binds to the telomere, and a catalytic subunit with reverse transcriptase activity, which adds the specific DNA sequence to the chromosome ends each time a cell divides.

Telomeres

Telomerase

Telomerase is repressed in most normal cells, allowing telomere length to gradually decrease and preventing uncontrolled proliferation. In tissues that have a high turnover throughout life, such as blood and gut, telomerase can be transiently upregulated in progenitor cells to maintain telomeres and enable controlled, self-limited proliferation to replace cells lost through natural processes. As the progeny of progenitor cells mature, telomerase is downregulated and telomeres shorten with cell division, preventing uncontrolled proliferation.

The 2009 Nobel Prize for Physiology or Medicine was awarded for the discovery of how chromosomes are protected by telomeres and the enzyme telomerase. The Nobel laureates were early Geron collaborators, Elizabeth Blackburn, Carol Greider and Jack Szostak.

A Hallmark of Cancer

A fundamental trait of cancer cells is the ability to sustain chronic and uncontrolled proliferation, as described in the recent paper: “Hallmarks of Cancer”.

Telomerase expression has been found to be present in approximately 90% of biopsies taken from a broad range of human cancers. Through the abnormal and sustained upregulation of telomerase, malignant cells acquire cellular immortality and avoid apoptosis, enabling the continued and uncontrolled proliferation that drives tumor growth and progression.

Normal Cells

Cancer Cells

A Molecular Target in Oncology

We believe that inhibiting telomerase may be an attractive approach to treating cancer because it may limit the proliferative capacity of malignant cells. Hematologic or blood cancers arise from malignant progenitor cells in the bone marrow and may be particularly susceptible to telomerase inhibition. Telomerase activity has been observed to be significantly increased and the average telomere length to be significantly shorter in patients with certain hematologic malignancies compared with healthy individuals. In addition, high telomerase activity has been associated with shorter overall survival of patients in some hematologic malignancies.

We developed imetelstat as a potential cancer treatment to inhibit telomerase activity and thereby impede proliferation of malignant cells.