“We found that 4-methylumbelliferone (4-MU) was able to block a key signaling pathway that triggers the development, growth and metastasis of prostate cancer,” said the study’s principal investigator Vinata B. Lokeshwar, Ph.D., professor of urology and director of the pilot and translational studies component of the Miami Clinical and Translational Science Institute. “The results were simply amazing.”
The study, “Dietary Supplement 4-Methylumbelliferone: An Effective Chemopreventive and Therapeutic Agent for Prostate Cancer,” was published this week in the Journal of the National Cancer Institute. Miller School co-authors were graduate student Travis Yates, Ph.D., research associate Luis Lopez, UM undergraduate student Soum Lokeshwar, urology resident Nicolas Ortiz, M.D., postdoctoral fellow Georgios Kallifatidis, Ph.D., graduate student Andre Jordan, masters student Kelly Hoye, and Norman Altman, VMD professor of pathology.
Prostate cancer is the most common cancer in men and accounts for 14 percent of all cancer cases. According to the National Cancer Institute’s estimates, in 2014 there were 233,000 new cases and about 30,000 deaths from prostate cancer and the projections for 2015 are similar. This amounts to the diagnosis of a new prostate cancer case every 2.3 minutes and a death from prostate cancer every 18 minutes, according to the Prostate Cancer Foundation.
Prostate cancer is diagnosed largely on the basis of the levels of a protein in blood, the prostate specific antigen (PSA). About 70 percent of the patients diagnosed with prostate cancer survive more than 10 years following curative treatments such as surgery, radiation or a combination of the two. Patients with low-risk/low-volume disease may opt for active-surveillance where surgery or radiation is delayed until the disease progresses. However, the disease recurs within two to eight years in about 30 percent of patients. Once relapsed, the disease is highly aggressive and metastasizes to bone in the later stages, causing debilitating morbidity and mortality. The current treatments are only palliative for metastatic prostate cancer.
“A large percentage of patients develop metastasis and ultimately die from it,” said Lokeshwar. “However, since prostate cancer is a slow progressive disease, our hypothesis was that it should be amenable to preventive strategies using dietary supplements which when started early may delay treatment and enhance survival while also improving patients’ quality of life.”
The research team had previously observed some anti-cancer properties of 4-MU against prostate cancer cells. “Since it is non-toxic and readily consumed to improve liver health and gall bladder function, 4-MU was the best preventive agent on hand to test our hypothesis,” said Lokeshwar, who has focused her research on understanding the mechanisms of bladder, kidney and prostate cancer progression.
4-MU has been known to inhibit the synthesis of hyaluronic acid (HA), a sugar polymer. Years of prior research in Lokeshwar’s laboratory found that the HA family of molecules promotes prostate and bladder cancer cell growth, their invasive activities and induces angiogenesis (the growth of new blood vessels that feed the tumor). 4-MU shuts down these processes by inhibiting HA synthesis.
The researchers initially decided to test the preventive and therapeutic potential of 4-MU in a transgenic mouse model of prostate cancer that mimics prostate cancer development and progression in men. Choosing a dose of 4-MU that is comparable to what is consumed as a dietary supplement, the two lead authors on the manuscript, Yates and Lopez, began treating these mice at distinct stages of the disease – low-volume/low-risk (eight weeks), clinically localized moderately differentiated prostate cancer (12 weeks) and aggressive disease (22 weeks) – and stopped the treatment at 28 weeks.
“We found that when treatment started early, at eight or 12 weeks it completely inhibited prostate cancer development and growth,” said Yates, who was a graduate student of the Sheila and David Fuente Graduate Program in Cancer Biology and is currently a postdoctoral fellow at the University of Pennsylvania. “At 22 weeks, we found small cancers that had stopped growing and even regressed in some cases. Also to our amazement, while 60 percent of the animals in the control group experienced metastasis to distant organs, none in the treatment group developed metastasis. 4-MU did all of this without causing any toxicity to the host.”
Encouraged by the results, the researcher went a step further. After stopping the treatment at the 28th week, they continued to monitor half the number of mice without treatment to see whether prostate cancer developed at all in these mice. “4-MU indeed offered a protective effect, but it was dependent upon when the treatment started; the earlier the treatment began the better the protection and so the mice in the eight-28 week treatment group did not develop prostate cancer at all, while in the late-stage treatment group this protection lasted for some months,” Lopez said.
Pathology examination conducted by Altman and other histological studies conducted by Soum Lokeshwar confirmed that 4-MU had halted the growth of new blood vessels, thus cutting off the nutrient supply to prostate tumors and reversing their ability tometastasize.
When Lokeshwar submitted this progress to the National Cancer Institute, which funded the study, Program Officer Suzanne Forry, Ph.D., suggested testing more models of prostate cancer to confirm the preventive and therapeutic potential of 4-MU. The researchers tested the effect of 4-MU in a mouse xenograft model of prostate cancer that develops bone metastasis similar to late-stage prostate cancer patients. Once again, 4-MU prevented and inhibited bone metastasis in this model, and even after stopping the treatment, mice did not develop bone metastasis. 4-MU also halted tumor growth in another prostate cancer model.
“As scientists, we always want to know why a drug works, because if we can unlock that secret then we can find ways to make it better or find alternatives if the drug fails,” said Lokeshwar. It took her and the rest of the team two more years to map the mechanism by which 4-MU exhibits a potent preventive and therapeutic “one drug two-punch” against prostate cancer. Lokeshwar gives much of the credit to her team, especially Yates and Lopez. The two came into the lab every day for nearly a year to give 4-MU to mice, even on holidays, in the hopes, they said, “it will make a difference in someone’s life.”
Lokeshwar said these pre-clinical studies on aggressive models of prostate cancer combined with the mechanistic studies should lay the groundwork for clinical trials with 4-MU. “We hope that this process can move forward because 4-MU has a long history as a safe oral nutritional supplement,” she said.
Sylvester Comprehensive Cancer Center at the University