prostate cancer discovery


Target: Hedgehog Pathway
New Trial Opens for Men with High-Risk Prostate Cancer


Why are urologists getting excited about a pathway named after a hedge - hog? Because this critical signaling pathway (discovered in mice with prostate cancer in 2005 by 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, M.D. Ph.D., Assistant Professor in Urology, Oncology, and Pathology, 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. 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 is an antifungal drug. Recently, new, Hedgehog pathwayspecific drugs with much more favorable toxicity profiles are available.”


Ross, with oncologist Emmanuel Antonarakis, is beginning a randomized, plabeco-controlled clinical trial of a highly selective Hedgehog pathway inhibitor, called LDE225 and made by Novartis. “The men who receive the drug will take it orally in pill form for four weeks.” Men will begin taking the inhibitor about a month before radical prostatectomy. All of the men will undergo a repeat biopsy and will 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 this new drug actually gets into the prostate and inhibits the Hedgehog pathway as we expect it should. 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 highrisk prostate cancer: men with a Gleason score of 8 to 10, a PSA of 20 or greater, or clinical stage T3 disease. In patients who have high-risk prostate cancer, there is always 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 “micr ometastatic” 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 like we treat other cancers, with a systemic approach in addition to surgery and/or radiation.”

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