Cholesterol-lowering drug tested for effect on prostate cancer tumors

A new clinical trial at MUSC Hollings Cancer Center will investigate whether a common statin – a drug used to lower cholesterol levels – affects an immune system pathway that could lead to a stronger anti-tumor response in patients with prostate cancer.

“There’s been a long-standing, consistent inverse association between statin use and a reduced risk of aggressive prostate cancer and, more recently, prostate cancer mortality,” explained Hollings researcher Michael Marrone, Ph.D. “It’s just been unclear in those observational epidemiological studies whether that inverse association is due to cholesterol reduction or some other non-cholesterol pathway. So, the focus of this trial is to investigate a specific non-cholesterol pathway through which statins might be contributing to reduced risk of aggressive prostate cancer.”

For this study, Marrone, a translational epidemiologist, is teaming up with Stephen Savage, M.D., vice chairman of the Department of Urology, who focuses on urologic cancers.

Savage has participated in many multidisciplinary trials, including a long-term trial looking at the role of vitamin D in prostate cancer. When Marrone, who joined MUSC last year, met Savage, he was excited about the potential for collaboration.

“I felt like that was a natural synergy there with that prior experience,” Marrone said.

Being able to work with people from different disciplines and to bring ideas from the lab into the clinic is one of the great opportunities of working in an academic medical center, Savage added.

“It keeps you excited and interested,” Savage said – especially when there’s a direct impact on patients.

"The focus of this trial is to investigate a specific non-cholesterol pathway through which statins might be contributing to reduced risk of aggressive prostate cancer.”

Michael Marrone, Ph.D.

And there will only be more of this type of collaboration, Marrone said.

“Having that kind of impact is what excites everyone at research institutions. And in order to have that kind of impact, you have to reach out and collaborate with people who have different expertise,” Marrone said. “Whereas if you’re segregated or siloed into your discipline, you can only do so much.”

In this trial, newly diagnosed prostate cancer patients will be signing up to potentially take the statin simvastatin for eight weeks before getting surgery. Because there are so many statins in use, with some 35 million Americans taking them, it was important for participants in the study to all take the same statin, Marrone said.

The participants will be randomized so that half get the statin and half do not. After surgery, their tumors will be examined and compared between both groups. Because of the relatively short time frame that the participants will be taking the medication, Marrone doesn’t expect to see differences noticeable to the naked eye, like a difference in tumor size. Instead, they’ll be looking to see if the statin has influenced an anti-tumor immune response.

Regulatory T lymphocytes, or Tregs, prevent the body’s immune system from attacking its own organs and tissues. Normally a good thing, this system backfires when Tregs proliferate in the tumor microenvironment and suppress an immune response against the cancer.

The Tregs need a transcriptional regulator called yes-associated protein, or YAP, to do their jobs. Without YAP, they don’t do as good of a job at keeping the immune system at bay. At the same time, statin drugs have been shown to inhibit YAP. So upon examining the tumors, Marrone hopes to see that the patients who took statins have a more robust anti-tumor immune response because the Tregs were forced to stand down.

Eventually, he’d like to see if statins can overcome the “cold” prostate cancer tumor environment and enable immune therapy to work. Tumors are characterized as “hot” or “cold” depending on how much immune system activity there is around them. Cold tumors are surrounded by cells that suppress the immune response and, as a result, generally don’t respond to immunotherapy.

“We believe that statins might be used to overcome the immunologically cold tumor environment,” Marrone said. That could mean they could help immune checkpoint inhibitors to work in men with prostate cancer.

“We won’t be able to necessarily answer that question with this trial, but hopefully, we’ll be able to generate some of the preliminary findings to determine whether or not there is this potential role for statins,” he said.

Savage and Marrone said that working across disciplines is important, not just for teasing out the biology of a cancer but also the reasons for disparities in outcomes among different groups. With prostate cancer, for example, the rates of this cancer are twice as high for Black men in South Carolina as for White men, and deaths from prostate cancer are almost three times higher for Black men than White men.

However, because South Carolina has a larger percentage of Black residents than the national average, and because the MUSC Health network is expanding to regional hospitals throughout the state, allowing it to serve people in rural areas more effectively, Hollings is in a position to find answers to these questions about disparities.

“We have a much larger minority population, and so the ability for us to identify how this type of intervention may impact a variety of minority or underserved populations is interesting,” Savage said.

Further, he has found that his Black patients tend to be very willing to participate in clinical trials like this one, even though the benefit to an individual patient is likely to be small because the study is gathering preliminary data.

“I explain to them what the clinical trial means and what impact it has on them, which in many cases is very little, but there’s potential benefit to have a greater understanding for their population,” he said. “I tell them this is an opportunity to address diseases that are disproportionally affecting this population, which has been understudied. So, it’s been neglected. And so, when they see that as an opportunity rather than an imposition, or worse, an experimentation, they sign up.”

The trial will open shortly at Hollings, then will be expanded to the Ralph H. Johnson VA Medical Center, where Savage also sees patients.

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