Regulation and manipulation of hTERT/telomerase splicing in cancer cells
The enzyme telomerase is expressed in most cancer types, making telomerase a highly attractive potential therapeutic target for producing stable cancer remissions. Furthermore, telomerase is a hallmark of cancer cells and understanding how telomerase is regulated may point out other specific features of cancer cells that can be targeted for therapeutic purposes (i.e., finding the Achilles’ heal of cancer or cancer cell dependencies). We hypothesize that shifting the splicing of hTERT mRNAs from activity producing transcripts to transcripts that do not generate active telomerase may shorten telomeres in cancer cells and produce long term stable cancer remissions. To this end we have identified splicing factors and cis elements that cancer cells utilize to promote the production of full length TERT mRNAs. Further, research will utilize this knowledge to block the binding of these proteins to their cis elements to reduce full length TERT, reduce telomerase activity and shorten telomeres. By developing a thorough understanding of the molecular regulation of TERT splicing we may be able to identify novel targets for therapeutic purposes. The ultimate goal of this project would be to develop therapies for cancer (reducing telomerase). Currently this project is funded by a National Cancer Institute Pathway to Independence award (K99/R00). We are in the first of three years of the R00 phase of funding.