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A man’s prostate cancer has spread, so he starts hormone treatment. At first, it works well. His PSA, a blood test doctors use to track the cancer, drops sharply. But after a year or two, the PSA shoots up. The cancer may have stopped responding to treatment.
“It’s truly an unmet medical need. If you get to that stage of prostate cancer, there is really no cure,” said James Sacchettini, Ph.D., a Texas A&M AgriLife Research scientist and the Rodger J. Wolfe-Welch Foundation Chair in Science. He is a professor in the Texas A&M College of Agriculture and Life Sciences Department of Biochemistry and Biophysics and College of Arts and Sciences Department of Chemistry.
Sacchettini and Chendil Damodaran, Ph.D., professor at the Texas A&M Irma Lerma Rangel College of Pharmacy, are leading a five-year, roughly $2 million National Institutes of Health collaboration in a search for new substances that target advanced prostate cancer.
The team will evaluate a vast collection of natural products — from plants, marine life and microbes gathered around the globe — looking for those that can shut down the disease while limiting toxicity in cells and animal models.
Why the drugs stop working
Prostate cancer is the most common cancer diagnosis in men in the U.S. Usually prostate cancer is found while it’s confined to the prostate, and it’s treated with surgery and radiation.
But if the disease returns after the initial treatment, or has spread, hormone therapy is used. Testosterone activates a protein called the androgen receptor, which allows the cancer to grow. Hormone therapy removes testosterone, either through surgery or drugs. The disease slows.
But in about one in five men on hormone therapy, cancer cells start to create a permanently turned-on version of the androgen receptor, called AR-V7. The cancer resurges. Doctors call this stage castration-resistant prostate cancer. There is no definitive treatment.
Damodaran said this has kept him working on prostate cancer for two decades, adding that this cancer is one of the strangest in how it travels from the prostate to the bones and the brain, in ways nobody fully understands.
The cost of the only option
Even when it works, hormone therapy carries a cost.
Removing testosterone changes a man’s whole body. Hormone therapy can bring fatigue, weight gain, changes to sex drive and a host of other side effects, according to the National Cancer Institute.
Many patients resist taking the treatment for that reason. Damodaran said this is part of why he wants a different approach, one that goes after AR-V7 directly rather than stripping away hormones and hoping the cancer does not adapt.
“We are targeting a different pathway, which may have different effects,” Damodaran said.
“If we can really help stop this cancer, we will make a big difference in people’s lives, and that’s important.”
James Sacchettini, Ph.D.
Scientist and Rodger J. Wolfe-Welch Foundation Chair in Science
AgriLife Research
The work to come
At the core of the project is the National Cancer Institute’s natural products collection. The largest such publicly accessible library, it houses hundreds of thousands of natural extracts collected worldwide over decades. Many current anti-cancer drugs started as natural products.
“We like natural products because the pathway to Food and Drug Administration approval can be shorter and toxicity can be cut back quite a bit,” Sacchettini said.
Damodaran’s and Sacchettini’s teams have also built a way to measure a compound’s activity against AR-V7 and cancer cells. They have already run preliminary screens against several thousand molecules.
The process will be ramped up to search the library. That work will be performed by scientists at the National Center for Advancing Translational Sciences, another part of the National Institutes of Health.
After receiving the data, Damodaran’s and Sacchettini’s teams will follow up with biochemistry and pharmacology. Sacchettini said they will use the data to work out exactly how the compounds function at a molecular level and deepen the understanding of prostate cancer biology.
“Nobody has ever taken on a screen of this magnitude to alleviate prostate cancer,” he said.
Overcoming limitations
A major caveat is that the work is many years away from reaching patients. Substances from turmeric, green tea, pomegranate and a long list of other natural products have shown promise against prostate cancer in the laboratory. None has become a drug yet.
Curcumin, an active ingredient in turmeric, is a cautionary example, Damodaran said. In previous clinical research, patients became ill taking the large doses required, and the substance still didn’t reach the bloodstream.
The team has designed the project to avoid outcomes like that. Every promising candidate will be tested against healthy prostate cells, so anything that harms healthy cells gets cut early rather than after years of work.
“Most people choose compounds simply on potency,” Sacchettini said. “We don’t believe that’s the best way forward.”
Damodaran said the Texas A&M and NIH scientists will meet every three months to discuss results.
“This is a very ambitious project,” he said. “But we are confident because of our combined expertise, the natural product library and our infrastructure.”
“If we can really help stop this cancer, we will make a big difference in people’s lives, and that’s important,” Sacchettini said.
Research reported in this publication was supported by the National Cancer Institute of the National Institutes of Health under Award Number UG3CA311400. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
