Vitamin D Studied to Treat Advanced Prostate Cancer
Division of Cancer Prevention
Some unanswered questions remain about the link between Vitamin D and cancer risk, which continues to be a priority research topic.
People primarily generate vitamin D3 when their skin is exposed to ultraviolet B radiation from the sun, explained Candace S. Johnson, Ph.D., deputy director and the Wallace Family Chair in Translational Research at the Roswell Park Cancer Institute in Buffalo, New York. Dietary vitamin D – found in eggs, fish and fortified dairy and cereal products – is usually inadequate so that people who live further from the equator and those who spend less time outdoors have higher rates of vitamin D deficiency, she added.
Dr. Johnson, and her colleague Roswell Park CEO Donald “Skip” Trump, M.D., have been pioneering ways to explore the vitamin D link to cancer risk, particularly in prostate cancer. In an earlier phase II trial*, more than 30 percent of men had their prostate-specific antigen (PSA) levels reduced by at least half, after taking a synthetic physiologically-active analog of vitamin D (1,25 dihydroxycholecalciferol) known as calcitriol. The vitamin D compound was given along with dexamethosone (one of the synthetic hormones known as glucocorticoids), which appeared to improve the impact of the drug, probably by increasing the amount of vitamin D receptor (VDR) that is expressed on most of the body’s cells, including cancer cells.
In her current NCI-funded research**, Dr. Johnson and her colleagues are looking at men with castration-resistant prostate cancer whose disease has usually spread (metastasized) and is growing without restraint. “Many of them have persistent bone pain and are feeling pretty lousy,” she noted. Most of these patients were originally treated with radiation or surgery, and now hormone therapy is no longer effective.
“Many of the men in our earlier trial felt better and had less bone pain after treatment with combination of calcitriol and dexamethosone,” explained Dr. Johnson. “We need to know more about what is happening at the molecular level, so that we can determine how much calcitriol we can give them safely, and the best way to administer it.” It turns out that blood levels of vitamin D do not simply rise when you give higher doses of calcitriol in some people. “I think that the dosing schedule may be a crucial part of the vitamin D puzzle,” she said. Early results suggest the best strategy might be to give very large doses for one or a few days, followed by 4 or more days off.
So far, it seems, the more calcitriol, the greater the impact on the cancer and its symptoms, Dr. Johnson added. However, within minutes of calcitriol entering the bloodstream, the cyp24 gene is activated and starts a process that breaks down calcitriol. Dr. Johnson and her colleagues are now looking to add a third drug, ketoconazole, to the combination, with the idea that ketoconazole will turn off induction of cyp24 and thereby increase the amount of calcitriol actually getting to the prostate tumors.
“We’re looking at the whole sequence of events from every angle that we can,” Dr. Johnson said. If their current phase II trial provides good information about dosing and effectiveness of calcitrol in combination with the two drugs, it may eventually lead to another treatment option in prostate and other solid tumors, she added.
* Trump DL, Potter DM, Muindi J, Brufsky A, Johnson CS. Phase II trial of high-dose, intermittent calcitriol (1,25 dihydroxyvitamin D3) and dexamethasone in androgen-independent prostate cancer. Cancer, May 15, 2006;106(10):2136-42.
**Grant Number: 5R01CA85142-10