Can an Antifungal Drug Work on Advanced Prostate Cancer?

Several years ago, scientist Jun Liu, Ph.D., had a brilliant idea: Because it can take years and many thousands of dollars to develop a new cancer drug from scratch, why not take a second look at drugs that have already been approved by the FDA? Maybe some of them could work against cancer, too. Already, this work is paying off. During an investigation of a well-known antifungal drug, itraconazole, 
Liu made two unexpected discoveries. First, he found that itraconazole is capable of blocking the formation of microscopic tumor blood vessels, a process known as angiogenesis. Second, itraconazole also blocks an important pathway called Hedgehog, a series of chemical messaging that occurs normally in the developing embryo that can be hijacked by cancer cells to promote their growth and metastasis. 

Liu's findings generated immediate interest, particularly in oncologist Emmanuel Antonarakis, M.D. Because both angiogenesis and Hedgehog signaling are known to be important for the growth and spread of prostate cancer – and because men with advanced prostate cancer are badly in need of a drug that can control the cancer when hormonal therapy stops working – Antonarakis decided to test itraconazole in men with metastatic prostate cancer that had become "castration-resistant" – no longer responsive to hormonal therapy. Antonarakis and his team of clinical investigators randomly assigned 46 men to receive either 200 mg of oral itraconazole daily or 600 mg of itraconazole daily, on a continuous basis. "Encouragingly, we found that 35 percent of the men receiving low-dose itraconazole had reductions in their PSA levels after starting treatment," Antonarakis reports. The men who got the higher dose of itraconazole did even better: "We observed PSA reductions in 54 percent of these men." 

In addition, the tumor got smaller in 15 percent of the men on low-dose itraconazole and in 28% of men on the higher dose. "Intriguingly, 62 percent of all men receiving itraconazole (low-dose and high-dose combined) had reductions in the number of cancer cells traveling in their circulation (called "circulating tumor cells") that were measured using an experimental technique." 

After a more detailed analysis, Antonarakis and colleagues confirmed that the best responses were observed in men receiving the high-dose itraconazole. "In fact," he notes, "there was a direct correlation between higher blood levels of this drug and better clinical responses. The team also found that the higher blood levels of itraconazole resulted in stronger suppression of the Hedgehog pathway, which was examined by obtaining skin biopsies from each patient before and after treatment was started. "This finding suggested for the first time that blocking the Hedgehog pathway may be a very fruitful endeavor in men with prostate cancer." (This idea was first proposed in 2005 by David Berman, M.D., Ph.D. and Philip Beachy, Ph.D., who discovered the critical role of Hedgehog signaling while studying mice with prostate cancer. Discovery has covered Berman and Beachy's ongoing research in previous issues.) 

Very encouraged by these results, Antonarakis and colleagues plan to test highdose itraconazole in men with less advanced prostate cancer. Their next study, expected to begin in the next few months, will focus on patients whose PSA has returned after prostatectomy who have not yet received hormonal therapy. They expect that the clinical benefit of itraconazole in these patients may be even more pronounced. Their ultimate goal is to determine whether taking itraconazole may delay or prevent the development of metastases in these men.

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