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Johns Hopkins Urology - Target: Hedgehog Pathway

Johns Hopkins Urology Fall 2014

Target: Hedgehog Pathway

Date: October 16, 2014

New trial opens for men with high-risk prostate cancer.


Ashley Ross and Emmanuel Antonarakis with tissue section blocks of patient prostate cancer cells.
Ashley Ross and Emmanuel Antonarakis with tissue section blocks of patient prostate cancer cells.

Why are urologists excited about a pathway named after a hedgehog? Because this critical signaling pathway—discovered in mice with prostate cancer in 2005 by Johns Hopkins scientists David Berman and Philip Beachy—is known to be important for the growth and spread of prostate cancer. And, says urologist Ashley Ross, because men with high-risk prostate cancer are badly in need of a drug that could potentially prevent cancer growth and metastasis by targeting this pathway.

“By looking at gene expression patterns, we and others have found that the Hedgehog pathway appears up-regulated in men with disease that metastasizes after local therapy,” says Ross. “Also, in men with advanced prostate cancer, itraconazole, which inhibits the Hedgehog pathway, appears to slow the disease by a mechanism independent of the androgen receptor. Itraconazole, an antifungal drug, is somewhat crude, but new Hedgehog pathway-specific drugs with much more favorable toxicity profiles are now available.”   

Ross and oncologist Emmanuel Antonarakis are beginning a randomized, plabeco-controlled clinical trial of a highly selective Hedgehog pathway inhibitor called LDE225. Men will begin taking the inhibitor about a month before radical prostatectomy. All will undergo a repeat biopsy and have a molecular profile done on their cancer cells before surgery, and then will have the radical prostatectomy specimens examined afterward.

“It’s a pharmacodynamic trial to see if LDE225 actually gets into the prostate and inhibits the Hedgehog pathway,” says Ross. “Of course, men will be followed closely following prostatectomy, and we will also monitor whether superior cancer control results are achieved in those who received LDE225.”     

The trial is open to radical prostatectomy patients at Johns Hopkins with high-risk prostate cancer: men with a Gleason score of 8 to 10, a PSA of 20 or greater, or clinical stage T3 disease. One worry with these patients is the possibility that, even after surgery or radiation therapy, some cancer cells have already escaped the prostate, are hiding somewhere in the body and will repopulate. Use of a systemic Hedgehog inhibitor may help wipe out these “micrometastatic” cells.

“We need to start thinking of high-risk disease as a different type of cancer,” says Ross, “a systemic disease, and we have to start treating them with a systemic approach in addition to surgery and/or radiation.”

To discuss a case or refer a patient, call 443-997-1851.

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