As many as one in eight men in America will be diagnosed with prostate cancer at some point in their lives. About one in 44 will die from it. “Prostate cancer is very common,” Cold Spring Harbor Laboratory (CSHL) Professor Lloyd Trotman says. “The vast majority of prostate cancers remain slow-growing and will never be life-threatening. The problem is that about 10 to 15 percent will be more aggressive and become resistant to therapy. To this day, it’s very hard to separate the two.”
Researchers have faced significant barriers to studying aggressive metastatic prostate cancer. Very few animals develop the disease naturally, and few methods exist to analyze how this type of cancer spreads throughout the body.
At CSHL, Trotman has been researching prostate cancer day in and day out for the better part of two decades. He’s the first to admit his work yields mostly incremental results—one small finding after the next. However, he notes, each step is crucial. His measured approach has led to multiple breakthroughs, including the first natural model for studying metastatic prostate cancer. Over the past decade, that model has helped Trotman make several important discoveries, including a potential new therapy set to begin clinical trials early next year.
“There is hope that cancer is entirely curable, and we’re just missing key pieces,” Trotman says. “The vision is that if we unlearn what we know, can we then discover how to actually cure it?”
Start with a problem
In the early 2000s, Trotman was a postdoc at Memorial Sloan Kettering Cancer Center. At the same time, a large team of researchers across the country was conducting a clinical trial to see whether antioxidants could hinder the development of prostate cancer. Over 35,000 men participated in the SELECT trial. It was intended to last up to 12 years.
However, in September 2008, an independent committee reviewing the data concluded that the antioxidant supplements being tested, vitamin E and selenium, do not prevent prostate cancer. A month later, participants were told to stop taking their supplements. Follow-up data published in 2011 suggested antioxidants actually had an adverse effect. There were 17 percent more prostate cancer diagnoses among participants who’d taken just the vitamin E supplements than those who’d taken a placebo.
Trotman found the results puzzling. Oxidants had long been associated with aging and disease. Antioxidants were seen as a way to slow these processes. “Everybody thought, ‘Antioxidants are great. Antioxidants keep you young,’” Trotman recalls. It turned out “the exact opposite is true, at least for prostate cancer.”
As the clinical trial was starting, Trotman had been looking to identify genetic mutations that interacted with mutations in another gene called PTEN to accelerate cancer in mice. PTEN is a known tumor-suppressing gene. When turned off or deleted, it’s strongly associated with metastatic prostate cancer. At that time, breeding a mouse that had a PTEN mutation with another mouse that had a different mutation was the best way to see how these two genetic abnormalities worked off one another.
In fact, it was the least bad option. The process was extremely slow and limited in scope. It could take four to five years to test and analyze just one potentially cancer-causing mutation. “It was clear that there were many more candidate genes that could be influencing cancer in a great way,” Trotman says. “We needed faster ways of validating or invalidating them.”
Furthermore, existing mouse models failed to consistently develop tumors that metastasized, making it difficult to study the most deadly and aggressive prostate cancers.
Try, try again
When Trotman came to CSHL in 2007, he was determined to come up with a better way to study metastatic prostate cancer.
His idea was to use a virus to deliver a gene mutation into a single cell in a mouse’s prostate. Researchers had already successfully used viruses to manipulate the genome in other tissues, like the lungs. But delivering one to the prostate required extremely precise surgical skills.
“Pretty much everybody in the lab at some point gave this a try,” he says. “The first attempts were really unsuccessful.” Still, along the way, they discovered that the virus that most efficiently brought genetic materials to the cells also triggered a strong immune reaction in the mice.
The lab kept working on the mouse model in the background for years, until lab member Hyejin Cho finally made a breakthrough. Two years into her Ph.D. studies, Cho had hit an unexpected roadblock that caused her project to fall through. However, her thesis work had required her to become an expert in viral infection techniques. So, Trotman asked if she wanted to tackle the mouse model for her dissertation. Cho accepted the challenge. Within a few months, she’d paved a new path forward.
By 2014, the lab had come up with a new mouse model called RapidCaP that could be used to test prostate cancer scenarios in just a few months. Trotman quickly realized something even more remarkable. Because tumors growing throughout the mouse bodies could be traced back to a single cell, the team had created the first natural model of metastatic prostate cancer.
“We had never been able to make convincing versions of metastatic prostate cancer in the animals,” Trotman says. “With this system, the mice actually died from metastasis.”
New data, new directions
With their new model, the Trotman lab began running more experiments to test how PTEN proteins interact with the body.
In 2015, they discovered that PTEN performs a kind of “bait and switch” by turning on an unexpected cancer gene called MYC. In 2018, they found that cells lacking the PTEN protein are particularly vulnerable to drugs called mitochondrial inhibitors. The inhibitors cause PTEN-lacking cells to consume vast amounts of sugar until they run out of energy and die. This idea is now being tested using the diabetes drug metformin.
Trotman also worked with then-CSHL Associate Professor Pavel Osten to develop a new method for capturing images of cancer cell growth in the RapidCaP model. The technique, called serial two-photon tomography, allowed researchers to create a 3D reconstruction of a mouse’s entire prostate and then track how cancer spreads within the organ.
Through it all, the clinical trial of the early 2000s remained on Trotman’s mind. Despite its failure to establish antioxidants as a viable therapy for prostate cancer, something told him that the study could still point to new therapies. He wondered, ‘If antioxidants were associated with an increased risk of prostate cancer, could patients take pro-oxidants to decrease their risk?’
New research from CSHL Professor Lloyd Trotman offers men of all ages a look inside the possible future of prostate cancer treatment and prevention.
His colleague, CSHL Professor David Tuveson, had data hinting at that very notion. “It showed that as much as pro-oxidants are dangerous to normal cells, cancer cells hate them even more,” Trotman explained. “For me, the question then became, ‘Now that we have our own little patients in the form of animal models, could we begin to identify better therapies?”
Immediately after publishing RapidCaP, Trotman started researching possible pro-oxidant therapies. A decade later, his lab’s efforts began to pay off in a big way. In 2024, they published a groundbreaking study suggesting that the pro-oxidant menadione, a precursor to vitamin K, slows prostate cancer progression in RapidCaP models. Menadione works by lowering levels of a lipid called PI(3)P in prostate cancer cells, which eventually causes the cells to die.
A lasting impact
Trotman aims to begin clinical trials in humans early next year.
“We’re taking it step by step,” he says. His first question: If a person diagnosed with carcinoma takes menadione for two to three weeks before prostate removal, will the patient show results like those seen in the mouse model? “It’s not really a therapeutic question yet,” Trotman says. “It’s simply a question of: Does the drug get there at all? Does it leave a trace?”
Approaching research carefully and incrementally has been a common thread throughout Trotman’s career. Many of his research projects have taken years to perfect. However, it’s his team’s diligence that gives him and others confidence in the results.
“Our key findings over the past 10 years are extremely solid. They can be built on to this day. All of that has to do with patience,” he says. “We could have published more if we had a more aggressive, short-term vision. And we would’ve failed the prostate cancer community if we’d given them something that sounded great but didn’t last. Instead, we chose to go the other way. The hope is that this will truly pay off when we now try all of this in patients.”
Written by: Margaret Osborne, Science Writer | publicaffairs@cshl.edu | 516-367-8455