March 29, 2017 | by Katie Neith
According to the American Cancer Society, prostate cancer is the second most diagnosed cancer in American men. While the disease is often treated successfully, it is still the third leading cancer killer among men and represents a huge health and economic burden. In addition, treatment can result in sexual difficulties, urinary problems and other side effects.
Now, a team from City of Hope believes they have found a key mechanism for potentially keeping the disease at bay, both before and after diagnosis.
“I think we found something really interesting in prostate cancer by identifying a new target for both treatment and potentially for prevention,” says Jeremy Jones, Ph.D., assistant professor of cancer biology at Beckman Research Institute of City of Hope.
In a January paper published in the journal Oncotarget, a team of City of Hope researchers led by Jones revealed an answer to a known question, “Why do men who use the blood thinner warfarin have a lower risk of prostate cancer?” The researchers believe they have figured out the molecular mechanism to explain why the drug appears to inhibit, or prevent the action of, two proteins, the androgen receptor (AR) and PPAR gamma, and why those proteins are important in prostate cancer development.
“We used the power of the ‘bedside to bench and back to bedside’ approach to research for this project in that we took a clinical observation — men who use blood thinner Coumadin have a lower risk of prostate cancer — and identified why this was happening at a molecular level,” says Jones. “I think we have a real, new target for prostate cancer in PPAR gamma, and we're hard at work developing novel drugs to target it.”
Further driving the team’s commitment to learning more about PPAR gamma, a group of scientists from the United Kingdom bolstered Jones and his colleagues’ findings by publishing a similar report in the Proceedings of the National Academy of Sciences journal just six months prior to the City of Hope paper.
“I have to say how incredible it was that two groups found this same target at nearly the same time by two completely different, unbiased approaches,” says Jones. “By unbiased I mean that we didn't go in to the experiment specifically looking to see if PPAR gamma was involved. Instead we took a genomic approach — whole transcriptome sequencing — and let the data tell us which proteins were likely involved.”
The finding that PPAR gamma plays a role in prostate cancer flips conventional thinking on its head, as the majority of previous research had suggested that activating, not inhibiting, PPAR gamma might be useful for treating prostate cancer.
“Our study, along with the PNAS study, clearly change this paradigm and show that PPAR gamma inhibition is crucial,” says Jones. “The obvious major implication is a new treatment for metastatic prostate cancer and a new preventive medicine to reduce the risk of developing prostate cancer.”
Jones, along with Sumanta Pal, M.D., medical oncologist and assistant professor in the Department of Medical Oncology & Therapeutics Research, and Catherine Elix, a graduate student at City of Hope’s Irell & Manella Graduate School of Biological Sciences — two City of Hope co-authors on the Onctotarget paper — are also working on a review comparing the findings from the related two papers and outlining what’s next. It will be published in an upcoming issue of the Asian Journal of Andrology. They say there are two major avenues to follow for pushing the PPAR gamma research forward; learning more about how PPAR gamma contributes to prostate cancer and develop novel molecules for inhibit the protein.
“Very few inhibitors for PPAR gamma exist, which is what we need for prostate cancer. We hope to raise the money to synthesize and test new inhibitors, and eventually identify one or several that have good drug-like properties in hopes of advancing them to clinical trials for prostate cancer treatment.”
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