Yet Another Approach to Blocking Telomerase Activity in a Broad Range of Cancers
Meaningful progress in cancer research in the decade ahead will emerge from strategies that can be applied to many different types of cancer: the same cost in time and money goes into development as building a treatment that is applicable to only one type, but the end result is vastly more effective and useful. The one commonality shared by all cancer cells is the ability to extend telomeres to permit uncontrolled cell replication past the normal limits. Take that away and the cancer fades. This is the SENS approach to preventing cancer by striking at the root, and the same strategy is emerging elsewhere in the research community. A variety of different approaches are under development, most focused on interfering in the activity of telomerase:
Approximately 85 percent of cancer cells obtain their limitless replicative potential through the reactivation of a specific protein called telomerase reverse transcriptase (TERT). Recent cancer research has shown that highly recurrent mutations in the promoter of the TERT gene are the most common genetic mutations in many cancers. TERT stabilizes chromosomes by elongating the protective element at the end of each chromosome in a cell. Scientists have discovered that cells harboring these mutations aberrantly increase TERT expression, effectively making them immortal.Researchers have identified that the mechanism of increased TERT expression in tumor tissue relies on a specific transcription factor that selectively binds the mutated sequences. A transcription factor is a protein that binds specific DNA sequences and regulates how its target genes are expressed (in this case the gene that expresses TERT). Thus, the TERT mutations act as a new binding site for the transcription factor that controls TERT expression. The newly identified transcription factor does not recognize the normal TERT promoter sequence, and thus, does not regulate TERT in healthy tissue.
The team's work further showed that the same transcription factor recognizes and binds the mutant TERT promoter in tumor cells from four different cancer types, underscoring that this is a common mechanism of TERT reactivation. The identified transcription factor and its regulators have great potential for the development of new precision therapeutic interventions in cancers that harbor the TERT mutations. A treatment that would inhibit TERT in a targeted cancer-cell-specific manner would bypass the toxicities associated with current treatments that inadvertently also target TERT in normal healthy cells. The team is now conducting a variety of experiments designed to test whether inhibiting the transcription factor activity would not only turn down TERT expression, but might also result in selective cancer cell death.
Very interesting. It remains to be seem how often cancers can develop resistance to this kind of treatments.
@Antonio: This one sounds more vulnerable to the development of resistance than other approaches I've seen. Removing much larger sections of necessary mechanisms, such as by attacking telomeres directly or by removing telomerase and ALT, should be invulnerable to the development of resistance. Then you have to balance doing this globally, and for how long, versus needing a targeting mechanism to get it to cancer cells only, of course.
I think the approach by Maria Blasco at the CNIO is the most promising personally, that lab is doing some amazing things with Telomeres. ONCOSENS in the making!