Scientists have long understood that testosterone fuels prostate tumors, a discovery that prompted the development of hormone-blocking “castration” treatments for prostate cancer that delay the cancer’s growth in many men.
But a new study shows that a certain type of prostate cancer, after months or years of testosterone deprivation, can develop a lethal sensitivity to testosterone in a new treatment approach – “bipolar androgen therapy” – which combines high-dose testosterone with androgen-blocking therapy.
Drugs that suppress natural production of testosterone can extend survival for men with prostate cancer, but eventually they stop working as the cancer becomes resistant to treatment. Known as castration-resistant prostate cancer, this advanced disease is the most lethal form, said Dr. Michael Schweizer, a clinical researcher at Fred Hutchinson Cancer Research Center.
Although men with early-stage prostate cancer can survive for many years with slow-growing tumors, if they live long enough, all men with prostate cancer will eventually develop this lethal form.
“There’s really a need for new drugs to treat these men,” Schweizer said.
In a small clinical trial of 16 men with castration-resistant prostate cancer, Schweizer and his colleagues at Johns Hopkins Hospital found therapeutic promise in sending these men’s testosterone levels on a rollercoaster ride from high peaks to low valleys. The researchers published their findings today in the journal Science Translational Medicine. Schweizer helped conduct the study during a recent fellowship at Johns Hopkins along with his fellowship mentor, oncology researcher Dr. Samuel Denmeade.
Fourteen of the 16 men completed the therapy, and many of those showed signs that their disease was waning. Some men’s tumors even appeared to become newly sensitized to those same castrating drugs that had previously stopped working.
The men in the trial, all of whom had metastatic cancer, had been taking testosterone-suppressing drugs up until their study enrollment. The men stayed on these drugs and then received injections of high-dose testosterone, each shot four weeks apart.
This combination of hormone injections with androgen-suppressing drugs gave the men sky-high levels of testosterone that declined to very low levels by the end of each monthly cycle – hence the term biopolar androgen therapy.
Seven of the 14 men showed dropping levels of prostate-specific antigen, or PSA, a molecule produced by prostate cancer cells that indirectly signals how vigorously tumors are growing. Of the 10 participants whose metastatic tumors could be measured by CAT scan, five had their metastases shrink while on the hormone treatment, Schweizer said. And one man’s tumors disappeared completely.
A potentially heretical idea
Since this was an early-phase trial and the first to try this seemingly paradoxical approach, one important takeaway for Schweizer was that none of the participants showed signs of their cancer worsening.
The idea that large amounts of testosterone, far higher than typically produced by the body, could stifle prostate cancer sounds somewhat heretical, Schweizer said. But he and his colleagues, and other research teams, previously found that prostate cancer cells similar to those in men with castration-resistant disease could be killed in the laboratory using such hormone fluctuations.
“We had a reason to believe that this would be an effective therapy. Of course you’re a little bit anxious doing a trial like this, because the teaching is that testosterone really drives prostate cancer. The analogy that some people might use is that it’s like throwing gasoline on a fire,” Schweizer said. “Fortunately we didn’t see the fire flare up.”
Schweizer stressed that the tumor cells likely first need to undergo certain changes – caused by long-term exposure to castrating drugs – in order for testosterone to transition from cancer fuel to cancer extinguisher. If it proves effective in larger studies, high-dose testosterone therapy will most likely only be appropriate for some men with prostate cancer, perhaps limited to those previously treated with androgen deprivation therapy.
It is important to note, Schweizer said, that this study was only available to men with no symptoms due to their cancer, in case the testosterone therapy worsened men’s symptoms. He also emphasized that high-dose testosterone needs to be further tested in larger trials, and the safety of the therapy ensured, before the treatment is ready for routine clinical use.
Denmeade and his colleagues are now launching a larger, phase 2 clinical trial of bipolar androgen therapy that they hope will open for enrollment by midyear. Centered at Johns Hopkins, the trial will have multiple recruiting sites, including one at Seattle Cancer Care Alliance led by Schweizer.
Although men in the pilot study also received etoposide, a chemotherapy drug, the next trial won’t include it. One elderly participant died from sepsis after one round of treatment in the trial. His death was likely a complication from the drug, Schweizer said, and the researchers don’t think the drug helped the testosterone to combat cancer. Two other study participants died since the trial began in 2010.
Improving quality of life
Hormone-suppressing therapies for prostate cancer carry a host of unpleasant and sometimes dangerous side effects. But the bipolar testosterone treatment had positive effects, especially given that the men in the trial had been on castrating therapies for years, Schweizer said.
The researchers didn’t conduct formal surveys on the men’s quality of life, but anecdotally, “the men who get these therapies really feel wonderful,” Schweizer said. “They were able to have sex again with their wives in some instances, energy levels went up; they lost weight, gained some muscle back.”
The participants’ temporary relief from the long-term effects of their past treatment was a boon for Schweizer too. He normally doesn’t get to test drugs with such pleasant associations.
“A lot of the drugs that we test in oncology have a lot of adverse effects … but this was definitely not one of those studies,” he said. “Right now we don’t think we can cure metastatic prostate cancer, so if you’re talking about trying to alleviate suffering, I think maximizing the quality of someone’s life is really important.”
Dr. Rachel Tompa, a staff writer at Fred Hutchinson Cancer Research Center, joined Fred Hutch in 2009 as an editor working with infectious disease researchers and has since written about topics ranging from nanotechnology to global health. She has a Ph.D. in molecular biology from the University of California, San Francisco and a certificate in science writing from the University of California, Santa Cruz. Reach her at firstname.lastname@example.org.
Solid tumors, such as those of the prostate, are the focus of Solid Tumor Translational Research, a network comprised of Fred Hutchinson Cancer Research Center, UW Medicine and Seattle Cancer Care Alliance. STTR is bridging laboratory sciences and patient care to provide the most precise treatment options for patients with solid tumor cancers.
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