The James Buchanan Brady Urological Institute
Volume VIII, Winter 2012
Research Offers New Potential Target for Chemotherapy

Discoveries about the genetics of prostate cancer may lead to new ways to attack the disease. The new findings, published in two prestigious medical journals, have to do with tiny breakages and repairs to the DNA that happen as cancer develops — and the discovery that the smart use of male hormones and drugs that specifically target this process may allow new, more effective ways to kill the most advanced cancer cells.

The possibility that male
hormones cause DNA strands to
break raises a new possibility:
That high doses of hormones may
be able to kill cancer cells.

Previously in Discovery, we reported on the work of scientists Bill Nelson, Vasan Yegnasubramanian and Michael Haffner in uncovering a particular problem that develops as prostate cancer advances. It’s a mistake that happens in the routine business of DNA, which is always in a state of transition in the body. “The major acquired defects in prostate cancer DNA appear to be rearrangements that occur as a result of accidental breaks in the DNA molecules,” says Nelson, M.D., Ph.D., Director of the Sidney Kimmel Comprehensive Cancer Center. “The idea is that if the breaks are repaired incorrectly, the broken DNA segment may be rejoined to the wrong site.”

In prostate cancer, a gene found in normal prostate cells, called TMPRSS2, which is regulated by male hormones (testosterone and its kin, dihydrotestosterone), breaks off from where it’s supposed to be and fuses with a gene called ERG, which is like a tiny version of the garden product, “Miracle Gro.” ERG causes cancer cells to flourish. Put it together with TMPRSS2, which responds to androgens, and the result can be catastrophic; this rearrangement happens in half of all prostate cancers. “The consequence of this mismatch is that prostate cells — now cancerous — acquire the propensity for invasive growth and dissemination throughout the body,” says Nelson. “What we discovered was that the action of the male hormones tended to trigger DNA breaks in specific sites at the TMPRSS2 gene, via some sort of error-prone attempt to initiate production of TMPRSS2.” Interestingly, this happens selectively in cells that are found in PIN — cells that are in between normal and cancer.

In an article published in Nature Genetics, Nelson, Haffner, and colleagues described their finding that male hormones cause a malfunctioning enzyme, called TOP2B, to become involved in this genetic mismatch. If this enzyme could somehow be blocked, it might offer a new opportunity for attacking prostate cancer. Also involved in this research were scientists Martin Aryeel, Antoun Toubaji, David Esopil, Roula Albadine, Bora Gurel, Bill Isaacs, Steven Bova, Wennuan Liu, Jianfeng Xu, Alan Meeker, George Netto, Angelo De Marzo, and Yegnasubramanian.

In another article, published in Clinical Cancer Research, Haffner, De Marzo, Meeker, Nelson and Yegnasubramanian proposed that hormone-cycling therapy, in combination with drugs that poison TOP2B or inhibit some of the other genes involved in DNA repair, could overwhelm cancer cells. An added benefit to this research is that this tactic may find headway where traditional chemotherapy drugs, which target rapidly dividing cells, have had limited success. As lethal as advanced prostate cancer can be, its cells divide fairly slowly compared to other cancer cells, and this has long been a roadblock for doctors trying to treat it.

“This finding has two important implications,” says Nelson. “First, the discovery of a male hormone-triggered process leading to gene defects provides a new insight into how such hormones contribute to the development of prostate cancer. Second, the possibility that male hormones trigger DNA breaks might be exploited — so we can kill cancer cells with high doses of the hormones.” This idea, he adds, is now under early testing, in clinical trials for men with advanced prostate cancer.

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