Project 467101

Telomeres are regions of repetitive nucleotide sequences located at the end of chromosomes to help preserve the integrity of the genome. These sequences are maintained by Telomerase, a large enzyme composed of an enzymatic component (hTERT) and an RNA component (hTERC). Telomerase activity is normally limited to embryonic gestation with essentially no activity in somatic cells. Consequently, telomeres shorten with age and cellular division which leads to senescence. In many cancers, including prostate, telomerase is highly expressed and preserves their telomeres which contributes to their longevity. As the rate-limiting factor for this enzyme is the expression of hTERT, its potential as a target for anti-tumor therapy is impressive. Historically, telomerase-targeting activities have been unsuccessful clinically but to bypass their shortfalls, we applied an unbiased genome-wide screen. This screen identified synthetic lethal interactions where inhibition of a gene is lethal only in the setting of hTERT overexpression. This created a shortlist of 30 potential targets which will be evaluated in multiple cell lines, primary cell lines, and xenograft models. Prostate cancer is clinically challenging disease to treat. The most common non-skin cancer in men, it is currently treated through hormonal deprivation therapy. In many cases, the cancer will adapt to resist this therapeutic challenge. Some pharmaceuticals exist to extend the lifespan of these patients, but frequently are insufficient to prevent the cancer progressing into more advanced disease. By using telomerase as a tool to guide therapy, rather than target it directly, we hope to overcome previous shortcomings with novel therapeutic targets in the treatment of prostate cancer.