Gene Fusion And The Development Of Drug Targets In Prostate Cancer

Main Category: Prostate / Prostate Cancer
Also Included In: Genetics;  Urology / Nephrology
Article Date: 20 Apr 2008 - 0:00 PDT

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UroToday.com - Dr. Mark Rubin spoke on gene fusion and the development of drug targets. A common, recurrent gene fusion between the TMPRSS2 and ETS transcription factor occurs in prostate cancer (CaP). TMPRSS2 is androgen regulated and specific to prostate cancer. The fusion is detectable in situ and can be applied to biopsies. The FISH assay can be used to identify the fusion in tissue samples, such as prostate biopsy. The fusion was found in 46% of cases using this technique. The TMPRSS2-ERG variant is the most common variant, and it occurs due to loss of DNA on chromosome 21, thus permitting the fusion. There are in addition at least 8 identified slice variants of this gene fusion. This adds complexity, as it is not known what the significance of these isoforms are. Cancer specific death was higher in men with these gene fusion on active surveillance for CaP.

Fusion was not identified in biopsies of BPH or atrophy, but was present in 16% of high-grade PIN, usually from adjacent CaP. 63% of the fusions occur through deletion, and 37% through insertion. The fusions are not associated with Gleason score. The gene fusion may improve the use of PCA3 to detect prostate cancer, and GenProbe is developing an assay for this. This, along with other biomarkers may be useful for predicting the presence of CaP. Other molecular alterations were not commonly found in conjunction with the fusion, but PTEN is one alteration found and is under investigation. An 87 gene signature map and conductivity map are being applied and estrogen control has emerged as potentially exerting some control over expression of the gene fusion. ETS transcription factors are a potential target, but 27 exist in most cells and half of them are active at any one time. Thus, drug targets for ETS may affect other processes. Specific ETS binding sites need to be targeted for greater specificity. Other targets include androgen and estrogen receptors. Treatment of gene fusion in CML has been beneficial and application to CAP is being pursued.

Presented by: Mark Rubin, MD, at the European Association of Urology - 23rd Annual EAU Congress - March 26 - 29, 2008 - Milan, Italy

Reported by UroToday.com Contributing Editor Christopher P. Evans, MD, FACS

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