Telomerase: Scientific Rationale

Nobel Prize Winning Science

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.

In the human body, normal growth and maintenance of tissues occurs by cell division. However, most cells are only able to divide a limited number of times, and this number of divisions is regulated by telomere length. Telomeres are repetitions of a deoxyribonucleic acid, or DNA, sequence located at the ends of chromosomes. They act as protective caps to maintain stability and integrity of the chromosomes, which contain the cell’s genetic material. Normally, every time a cell divides, the telomeres shorten. Eventually, they shrink to a critically short length, which prevents it from further cell division or leads to cell death (apoptosis).

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: a ribonucleic acid, or 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.

Telomeres

Telomerase

Telomerase is active during embryonic development, enabling the rapid cell division that supports normal growth. During the latter stages of human fetal development and in adulthood, telomerase is repressed in most cells, and telomere length gradually decreases during a lifetime.

A Hallmark of Cancer

A fundamental trait of cancer cells is the ability to sustain chronic and 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 enable controlled, self-limited proliferation to replace cells lost through natural cell aging processes. As the progeny of progenitor cells mature, telomerase is downregulated and telomeres shorten with cell division, preventing uncontrolled proliferation.

However in cancer, telomerase is upregulated in many tumor progenitor cells, enabling the continued and uncontrolled proliferation of the malignant cells that drive tumor growth and progression. Telomerase expression has been found to be present in approximately 90% of biopsies taken from a broad range of human cancers, thereby enabling tumor cells to maintain telomere length and providing them with the capacity for uncontrolled proliferation. Specifically in hematologic malignancies, telomerase enables the proliferation of malignant stem and progenitor cells which we believe are responsible for the underlying diseases and result in the production of dysfunctional and ineffective blood cells.

A Molecular Target in Oncology

Inhibiting telomerase may be an attractive approach to treating cancer because it may limit the proliferative capacity of malignant stem and progenitor cells, which are believed to be important drivers of tumor growth and progression. Many myeloid hematologic malignancies, or blood cancers, arise from malignant stem and progenitor cells that express higher telomerase activity and have shorter telomeres when compared to normal healthy cells. In vitro studies have suggested that tumor cells with short telomeres may be especially sensitive to the anti-proliferative effects of inhibiting telomerase. In addition, high telomerase activity has been associated with shorter overall survival of patients in some hematologic malignancies.

Samples obtained from patients in both Phase 2 IMbark and IMerge clinical trials indicated that imetelstat inhibited the uncontrolled proliferation of malignant stem and progenitor cells, resulting in apoptosis (cellular death) of malignant cells in the bone marrow and enabled bone marrow recovery and normal blood cell production.