For most men, it’s just a matter of time until an enlarged prostate compels more frequent trips to the bathroom, day and night. A new study from Children’s researchers and colleagues implicates circulating cholesterol and suggests a potential new prevention and therapeutic strategy. The findings are reported in the October Journal of Urology.
The paper is an interesting culmination of a story that goes back nearly 40 years. And granted, it’s a hamster study, but if the research is able to go forward, it could mean a new use for an existing cholesterol-lowering drug.
About half of men older than 50 (and 80 percent of men aged 80) develop enlarged prostates. The causes are unclear. In men and hamsters, the prostate nestles just under the bladder. Normally the size of a walnut, a chronically enlarged prostate can constrict the flow of urine, while also increasing the urge to urinate, creating pain and other symptoms.
The Children’s team studied a strain of Syrian hamsters that experience naturally enlarged prostates due to cholesterol metabolism problems–a good preclinical model for human benign prostatic hyperplasia–but the story began with dogs four decades ago.
Backstory: Nobel Prize and the King of Condoms
In the 1960s, study co-author Carl Schaffner, now professor emeritus at Rutgers University, was tasked with isolating the impurities in a topical treatment for vaginal yeast infections, and found that when he gave the same compound orally, it shrunk the normal prostates of laboratory rats and the enlarged prostates of old dogs. The active ingredient, the antifungal candicidin, had been discovered years earlier by a Rutgers colleague, who won a Nobel for related work.
Schaffner’s studies were sponsored by drug maker Julius Schmid, more famously known as the first U.S. condom manufacturer. Schaffner postulated that the main ingredient also prevented absorption of dietary cholesterol, which might have an effect on the prostate. “I thought oral candicidin would bind to cholesterol in the gastrointestinal tract,” Schaffner recalls.
In 1968, Schaffner and the company’s research director reported a marked reduction in the enlarged prostates in male dogs, as well as lowered cholesterol levels. Candicidin appeared to work by blocking cholesterol absorption from the gut and preventing it from accumulating in the prostate.
Candicidin made it as far as phase III clinical trials to treat benign prostatic hyperplasia, recounts Schaffner, and was approved as a treatment in some other countries, but sale of the company apparently derailed efforts toward U.S. approval.
“After the [U.S.] trials stopped, all the patients did their best to get the drug,” Schaffner remembers. “They wrote to the Philippines and ordered it from there. People brought it back from the former Soviet Union.” There was no other non-surgical alternative at the time.
A second chance
In 2002, Schaffner heard news of the Schering-Plough (now Merck) cholesterol-lowering drug ezetimibe (Zetia), the first FDA-approved drug to inhibit the absorption of cholesterol in the intestines, the same mechanism of action as candicidin. (Statins, which had become the mainstay of anti-cholesterol drugs, work by preventing the liver from turning fat into cholesterol.)
Meanwhile, at Children’s, Solomon and Michael Freeman, PhD, director of basic urologic research, had been studying the relationship between cholesterol and prostate disease. They met with Schaffner through a mutual scientific colleague, and invited Schaffner to Boston. They discussed cholesterol and the prostate for six hours straight.
Together, Children’s and Karikyon filed for patents for the uses of ezetimibe to treat benign prostatic hyperplasia and prostate cancer. Last year, the Children’s researchers reported that ezetimibe may delay prostate tumor growth in mice.
In the latest study, ezetimibe reduced the enlarged prostates of middle-aged hamsters to the same extent as the drug finasteride (Proscar, Propecia; Merck), which blocks the conversion of testosterone into the hormone that maintains the prostate. And combining the two drugs worked better than either one alone. In an unexpected finding, finasteride caused atrophy of the hamster prostate, while ezetimibe did not. The study was funded by the National Institutes of Health and the Hyde and Watson Foundation.
With an adult urology colleague in the Harvard medical community, the Children’s team designed a small clinical trial, hoping to measure with ultrasound the effect of ezetimibe on enlarged prostates, but they could not find funding.
With more support, Solomon and his colleagues would test lower doses of ezetimibe and of finasteride to see if the hamsters’ prostate symptoms could be relieved with fewer side effects, to see if cholesterol lowering could prevent enlargement, and to identify genes and proteins that mediate the effect of cholesterol on the prostate.
As the researchers seek further funding for their studies, Children’s Technology and Innovation Development Office seeks a business partner interested in developing the potential additional therapeutic applications in people. Merck’s dominant patent on the composition of ezetimibe patent expires on 2014. According to Maude Tessier, licensing manager at Children’s, business discussions are continuing with companies who might be interested in developing ezetimibe for prostate cancer and enlarged prostates.
“Hamsters don’t have the quality of life issues with enlarged prostates that men do,” Solomon says. “But they are particularly good at testing the role of cholesterol in prostate enlargement.”