In clinical trials, “clinical holds” are imposed by the FDA when toxicities emerge that are unexpected, either new toxicities that have not been seen before, (or were not anticipated) or increased severity of known or anticipated side effects. The hold allows the FDA to assess the data, demand more data from the sponsoring companies, and make appropriate changes in the study protocol…
In January 2014, a clinical hold was placed on imetelstat, a very promising drug that inhibits telomerase, due to liver toxicity. The hold has now been lifted permitting the resumption of a study at the Mayo Clinic in myelodysplastic syndrome, a bone marrow cancer in which blood cells do not form appropriately. The company is also conducting clinical studies in multiple myeloma and thrombocythemia, but clinical holds on those studies have yet to be lifted. (http://www.reuters.com/article/2014/06/12/us-geron-fda-idUSKBN0EN1IL20140612)
Telomerase is an enzyme that is very active in embryonic development. It does not allow chromosome ends to shorten, therefore, it immortalizes cells. One of the prerequisities of cancer, which is deregulated cell growth, is immortalization, the ability to divide without end.
Adult cells in the body undergo a finite number of divisions. The counter is the ends of the chromosomes, small pieces of which are lost after every division. After 50 or 60 cell divisions, the ends of the chromosomes have lost their telomeres, which causes genetic chaos in that the bare ends are now capable of fusing with each other in “breakage-fusion-breakage cycles,” which causes bizarre chromosomal arrangements, loss of genetic information, and genetic translocations. The genetic chaos continues on to induce “crisis” which is a signal to the cell to die via apoptosis. (Graphic by Robin Kramer, 2014)
Cancer cells benefit from the “chaos” because this creates a highly mutagenic state – cancer can accumulate mutations quickly in the setting of this significant genetic instability. When a cancer cell is able to re-invoke telomerase, which was made dormant after embryonic development, at this point, bad things happen. The chaos is stabilized and the cell does not proceed to crisis. All the mutations and translocations that occurred due to the bare telomeres are “locked-in,” and now these highly aberrant cancer cells are immortalized and dividing without end.
Telomerase becomes re-activated by mutation to the telomerase gene. The myc oncogenic transcription factor also induces telomerase activity, as does ER81, which is induced by the Ras-MAPK signaling transduction pathway. HPV virus protein E6 also induces telomerase. Again, telomerase activity is a critical characteristic of all cancers.
From a cancer biology point of view, imetelstat is a very important and promising compound. Blocking telomerase at the right time in the evolution of a cancer cell would stop it from accumulating additional mutations, for example, those that confer more aggressive behavior and the ability to colonize, or to resist treatment. Let’s hope that the safety signal that put the studies on hold do not torpedo the development of the product.