New takes on old targets
Telomerase reverse transcriptase (hTERT) is the catalytic subunit of telomerase, a famously intractable enzyme that has received extensive attention in the scientific community and the popular media because of its roles in oncology and the aging process. But telomerase has proven elusive as a therapeutic target. Reglagene’s approach to tackling telomerase as an oncology target illustrates the value of the program and the potential of QMST to exert far-reaching and unique impact in the discovery and development of new medicines.
Telomerase’s most well known role is to maintain telomeres, which are repeating DNA units that protect the ends of every chromosome. But a growing body of evidence supports a second role for hTERT, one that is critical for driving tumor growth and resistance to therapeutic intervention. Cancer cells translocate hTERT from the nucleus to the mitochondria, the powerhouses of the cell. In the mitochondria hTERT causes the buffering oxidative activity and the production of an agent that prevents cell death. Many scientific reports support the idea that this hTERT phenomenon occurs in response to therapeutic intervention to render cancer cells resistant. Many of these same reports show that repression of the hTERT gene causes cancer cell death and in several cases restores sensitivity to standard therapies.
The standard approach to cancer
Most healthy cells do not express telomerase. Exceptions are rapidly dividing cells such as stem cells and cells lining the gastrointestinal tract. However, ninety percent of all cancer types express telomerase.
The pharmaceutical industry long ago recognized the importance of telomerase as a target for the discovery of new cancer medicines. But without the benefit of understanding the other functions of hTERT (telomerase’s catalytic subunit), the industry created experimental therapies that inhibit the action of the fully formed telomerase enzyme to block its ability to maintain telomeres, the protective units on the ends of chromosomes. The enzyme inhibition approach failed clinically, with no medicines working by this route reaching the market.
A NEW WAY TO FIGHT CANCER
BY FIGHTING RESISTANCE
Reglagene’s approach to telomerase is different. We have agents that block the manufacture of hTERT by manipulating a quadruplex found on the gene. The result is that cancer cells make less hTERT, oxidative activity in the cancer cell sharply increases, and cancer cells die in days. To be clear, this effect is not achievable by the old strategy of telomerase enzyme inhibition. With the backing of small-business grants from the National Cancer Institute and the National Institute of Neurological Disorders and Stroke, we are pursuing therapeutic indications for metastatic prostate cancer and glioblastoma multiforme, an aggressive brain cancer that took the life of Arizona Senator John McCain. Our objective is to identify agents that delay or eliminate the onset of drug resistance for existing therapies.