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Gene fusion and prostate cancer development

Posted May 19 2010 12:00am


An article in today’s Israel Herald might give you the (incorrect) idea that androgen deprivation therapy is completely inappropriate as a  form of treatment for prostate cancer. Actually, that does not really seem to be what Yu et al. are implying if you look at the abstract of their recent article in Cancer Cell (on which the article is based). The article in the Israel Herald is apparently a reprint of a media release from the University of Michigan Comprehensive Cancer Center. One might have hoped for better from that normally reliable source.

It has been well understood for a while now that the fusion of two very specific genes the androgen-regulated gene TMPRSS2 and the oncogenic ETS transcription factor ERG occurs in about half the patients who have prostate cancer. But, as clearly stated by Yu et al., “how the fusion products regulate prostate cancer remains unclear.”

What Yu et al. seem to have been able to do is to develop a specific and testable model of how gene fusion may regulate the development of prostate cancer (at least in some patients). This is very important, and Arul Chinnaiyan, one of the study’s authors has been quoted as saying, “We need to begin to think about targeting prostate cancer by targeting the gene fusion, and not confining our approaches to [the] androgen receptor. If we’re going to find a more durable therapy, we need to get at the gene fusion.”

This is not quite the same as saying that “Gene fusion is the ‘smoking gun’ in the development of prostate cancer,” or that “Targeting the hormone androgen and its receptor in prostate cancer therapy could be a wrong approach after all.”

It is well appreciated that gene fusion can act as an “on switch” to trigger certain types of prostate cancer in some patients. In their most recent study, Yu et al. mapped the genome-wide location of the androgen receptor and the TMPRSS2-ERG gene fusion in prostate cancer cells. They have been able to show that gene fusion does actually block the androgen receptor directly and also interferes with the expression of the androgen receptor at a genetic level which can then affect normal androgen receptor signaling. If normal activity of the androgen receptor is blocked in this manner, prostate cells stop growing and developing normally, and this can lead to the development of prostate cancer cells.

“Our study shows the underlying problem in prostate cancer is the presence of a gene fusion, not the androgen receptor,” says Chinnaiyan. “In many contexts, androgen signaling is actually a good thing, but the presence of the gene fusion blocks androgen receptor signaling, which alters normal prostate cell development. While current treatments for advanced prostate cancer are focused on hormone deprivation and are quite effective, at least initially, future therapies need to be developed that target the prostate cancer gene fusion.”

Let’s not throw out the baby with the bath water. Androgen deprivation is a highly effective form of treatment for at least some men with progressive forms of prostate cancer. Is it perfect? No of course not. Do we need new and better therapies? Of course we do. And hopefully research of the type reported by Yu et al. will lead to such better therapies for patients with some types of prostate cancer. In the meantime, we will need to do the best we can with the treatments we have available today.


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