The male hormone testosterone can feed the growth of prostate cancer, but in an interesting twist, when given in a very specific way, it may also cause its demise. Drugs that block the action of testosterone are commonly used to treat men with advanced prostate cancer therapy. Cutting off the supply of testosterone to the cancer works for a time, but eventually prostate cancer cells figure out a way around it and begin to grow again. Other drugs work at the molecular level to cut off prostate cancer cells’ access to testosterone, but their impact is temporary and comes with unpleasant side effects. “Men who have long-term hormone ablation have a good response initially, but eventually they become resistant to therapy, and then there aren’t many options left for them,” says prostate cancer expert Samuel Denmeade. These are the men most at risk of dying from prostate cancer.

With testosterone viewed as a fuel for prostate cancer, most researchers are reluctant to explore it as potential therapy. However, what Denmeade and fellow prostate cancer researcher John Isaacs envisioned was different, and it all came down to the delivery. Taking a play right out of cancer’s playbook, Denmeade and Isaacs figured out what prostate cancer cells were doing to survive hormonal therapy and then beat them their own game. After prolonged treatment with testosterone-blocking drugs, prostate cancer cells adapted to living with low levels of the hormone by ramping up the activity and amount of receptors within the cell surface to suck up every bit of testosterone available.

With prostate cancer cells in this state, adapted to an environment with low levels of testosterone, Denmeade wondered what would happen if he flooded the cancer cells with a short burst of high-dose testosterone, using the hormone like a drug. “If we give testosterone acutely through injection to cause a sharp rise in the hormone, prostate cancer cells won’t like that, and some will die,” says Denmeade. “Prostate cancer cells might be killed by the hormone shock, and the cells that survived would make fewer receptors, making prostate cancer cells vulnerable once again to hormone-lowering therapies.” At first glance, it seems paradoxical to give testosterone to a prostate cancer patient, but Denmeade and Isaacs say this approach is very different from the chronic, ongoing supply of testosterone that naturally occurs in men or testosterone replacement therapy. “It’s pharmacologic testosterone, not physiological testosterone,” says Isaacs.

Prostate cancer cells are not expecting an intense dose of testosterone, and they don’t know that it’s a short burst. Cancer cells that survive will adapt again, this time turning down the activity of those cell surface testosterone receptors. “They will downregulate their receptors at a time when the drug is wearing off, so we will see a period of low testosterone, low receptor, and that’s not good for cancer cells,” says Denmeade. As the cells are continually challenged with these short bursts of testosterone, they are constantly adapting levels of cell surface receptors up and down. “We are taking the cancer cells’ options out of play by making the testosterone levels rise and fall rapidly,” says Denmeade. Denmeade turned the idea in a clinical trial of testosterone as a prostate cancer drug therapy. Following a pilot study funded by the One-In-Six Fund, the National Institutes of Health, and a $5 million Transformative Grant from the Department of Defense, he began to perform two studies—one at one at the Kimmel Cancer Center, and another at 18 sites across the U.S. Both clinical trials in asymptomatic men with prostate cancer that has progressed on hormone therapy were designed to see if a monthly injection of testosterone to make the testosterone level rise sharply for about a week would kill cancer cells.

Denmeade says about two-thirds of the men treated responded well to the therapy, at least keeping their prostate cancer stable. But Denmeade noticed that some of the men treated were resensitized to hormone therapy. That observation was the impetus for his Transformer Study, a new clinical trial to see if giving testosterone in sequence with hormone therapy could prevent or reverse hormone treatment resistance. One patient in the study had his cancer completely disappear for two years. Denmeade is now looking for biomarkers that predict which patients will respond best to the testosterone therapy. Prostate cancer expert Emmanuel Antonarakis identified a subset of patients with a variation in their cell surface receptors that predicts a more aggressive and resistant type of prostate cancer. Denmeade’s testosterone treatment may convert it to a less aggressive form of cancer. A new study, called the Batman Study, is funded by the Patrick Walsh Foundation, and is helping Denmeade and colleagues look more deeply into the specific molecular and cellular mechanisms that make this therapy work. With the exception of patients with prostate cancer that has spread to the bone, the short burst of testosterone makes most men feel better.

“Men were hugging me because they felt so good. People are clamoring for it,” says Denmeade. “We get emails from men all over the country and the world.” Denmeade says they are still learning about the best way to safely give the therapy. “So far, the side effects have been low grade, as long as the treatment is limited to men who are asymptomatic without any pain due to prostate cancer,” he says. “In some cases, the testosterone therapy makes men feel increased energy, less fatigue and restored sexual function.”

To date, 150 men have been treated with varying responses. “We have some patients whose PSA drops after treatment and their scans get better; we have others whose PSA doesn’t drop and even have some initial rises. For most patients, their prostate cancer is at least held in check,” he says. PSA stands for prostate-specific antigen. Tests that measure rising levels of PSA in the blood are used to screen for prostate cancer. Denmeade is studying cells from the one complete responder more closely in hopes it may provide critical clues. “If we can understand what happened in this one guy, it would provide a wealth of information,” he says.

One possibility is that the up and down of the testosterone attracts the attention of the immune system, which is always on patrol for things that look out of the ordinary. Deciphering what underpins these varied responses could reveal biomarkers that will help them decide who are the best candidates for the treatment and how long to give it. “There has been a groundswell of interest,” says Denmeade. “Right now, we have plenty of anecdotes and some evidence of how it works, but we need to do more research and test it in more patients.” The treatment with generic testosterone is a bargain at about $100 a month, but lacking a pharmaceutical partner, Denmeade and Isaacs are struggling to find funding to do additional combination studies. “Since we are using a generic form of testosterone we may have difficulty getting support from pharmaceutical companies,” says Isaacs. “So for now, it remains a completely homegrown project.”