Androgens, Arnold & New Targeted Treatments in Bladder and Breast Cancers
Have you seen early Arnold Schwarzenegger movies like “Platoon” or “Conan the Barbarian?” While they’re not necessarily groundbreaking cinematic achievements, these movies do a spectacular job of one thing: showing the power of hormone growth signaling.
What—did you think Conan was just naturally barbaric? Not so much. Instead, in addition to beefy genes and the growth signals of pumping iron, the former Mr. Universe supplied his muscles with then-legal anabolic-androgenic steroids that told his biceps to bulge and his triceps to take on the appearance of well-bred pygmy rhinos.
See, most of the 100 trillion or so cells that make up the adult human body spend much of their lives sitting around in lattices like inert little egg carton divots, forming the somewhat static structure and functions of your body. They sit like this until they’re told to grow, divide and proliferate. In males, the androgen known as testosterone tells cells to grow. The testes produce the bulk of it; it floats around in the blood; cells with the right receptors detect and gather it; and then these signaled cells react by turning on the their genetic growth machinery.
Unfortunately, in addition to the cells of the former California Governor’s musculature, there are cells in our body we would rather didn’t grow, namely cancer cells. And sometimes these cells have hijacked the same machinery—sometimes these cells have mutated to become so super-sensitive to androgen that even the body’s natural production creates signals that lead to the haywire growth of cancer.
Now researchers at CU Cancer Center are discovering more about how androgens drive diseases such as breast and bladder cancers—diseases for which pioneering work at CU first showed androgen’s role.
These discoveries from deep in the labs of our member institutions are allowing doctors in University of Colorado Health system clinics to target cancer’s dependence on androgen signaling in first round clinical trials. Knowing the cause of cancer’s growth allows doctors to target its demise.
Androgen Growth Signaling
Most humans have two arms, not four. We have ears but not horns, fingernails but not claws, and brains big enough to produce at least partial understanding of particle physics and Lady Gaga. This is because over many millennia we’ve adapted to our surroundings. Survival is an equation that balances the energy we consume against the energy we spend, and so your body has evolved to grow and maintain only the structures it needs.
But this means the body’s cells need to know their surroundings. In order to adapt, they need messages from the outside world. In large part, these messages come in the form of hormones. For example, when a cougar jumps from a tree into the trail in front of you, your body produces the hormone adrenaline. Your cells recognize this adrenaline signal and your lungs speed up, your blood vessels dilate to carry more nutrients, and you scream like the heroine of a zombie movie.
Cells’ sensitivity to their surroundings also has longer-term consequences. For example, a Northwestern University study found that the more hours per day a dad spends with his kids, the less testosterone he produces. The experience of fatherhood suppresses the production of testosterone in men by an average of 30 percent, leading to both decreased muscle building and a lower chance that fathers will eat their young (though we all know some days we’re tempted).
As previewed, some cancer cells also depend on testosterone signaling. Instead of affecting the production of testosterone, cancer cells tend to turn up the volume of growth signals produced by the testosterone that exists naturally in the body.
“In many ways, a cancer cell is a caricature of a healthy cell,” says CU Cancer Center Director Dan Theodorescu, MD, PhD. Think about the caricature artists you see on Denver’s 16th Street Mall on a sunny summer day: They draw subjects with every feature exaggerated. Likewise, “a cancer cell is like a normal cell, just with some features exaggerated—in many cases becoming more sensitive to signals that also drive the growth of healthy cells or less inhibited by signals that suppress growth,” Theodorescu says.
One way cancer cells become more sensitive to hormone signaling is by producing additional hormone receptors—hormones like testosterone float around the body but only the cells that can grab it with receptors get its message. The more receptors, the more hormone molecules the cell can grab and the more sensitive the cell is to the signal.
“The cell of a hormone-driven cancer might be completely loaded with these things,” Theodorescu says.
A Nobel Prize was awarded in the 50’s for the discovery that androgens and estrogens control cancer growth, most notably estrogens in breast cancer and androgens in prostate cancer. In prostate cancer, genetic mutations can make receptors super sensitive to androgen so when they grab testosterone, growth signals are grossly amplified. They’ve hijacked signals of healthy growth for their own unhealthy purposes. So the historical treatment for prostate cancer was to remove the source of testosterone production. Newer treatments use drugs to blunt this production or to plug cancer cells’ androgen receptors so they can’t grab their hormone targets.
This work in prostate cancer is the backdrop for current work in hormone-driven cancers, but since the early days of anti-androgens, new hormonal drivers and new ways to block them have taken center stage.
Androgen in Breast Cancer
About 70 percent of breast cancers are estrogen-receptor positive. (Note: estrogen, not androgen.) Rather than these cells containing molecules of estrogen as their name suggests, the label “estrogen-receptor positive” means that the cell contains receptors that grab any available estrogen. Estrogen-receptor positive breast cancer uses estrogen signaling to drive its growth.
“Adult cells in general are not supposed to be dividing unless they get a cue to tell them to divide. This is something the tumor takes advantage of—receptors can mutate to become ultra-sensitive, transmitting a growth signal that’s much more powerful than it should be. Sometimes the receptors are over expressed. Sometimes they get much better at trapping circulating hormones,” says breast cancer researcher, Jennifer Richer, PhD, associate professor of pathology and co-director of CU Cancer Center Tissue Biobanking and Processing Shared Resource.
A breast cancer cell that is hypersensitive to estrogen or another growth-inducing hormone sounds like a bad thing. However, a cancer’s sensitivity can be an addiction and, for example, estrogen-positive breast cancer can be combatted by anti-estrogen therapies, such as the drug tamoxifen. Specifically, this drug splits into molecules that bind to and plug a cancer cell’s estrogen receptors, stopping the growth signal from being transmitted. With receptors plugged, ER+ breast cancer cells can’t grab estrogen and without estrogen, these hormone addicted
cancer cells don’t grow and eventually die.
Estrogen isn’t alone—the growth of breast cancers can also be driven by progesterone receptors (PR+) or the HER2 (HER2+) growth factor receptor. In all cases, a hormone or growth factor driver provides a therapeutic target—without a driver, doctors are left with “triple-negative” breast cancer that seems to grow and proliferate even without signals from these hormonal and genetic culprits.
“Triple-negative is a clinical classification. It’s the way doctors treating the disease categorize it—no ER, PR or HER2—and it informs treatment decisions. But calling it triple-negative is a little misleading,” Richer says. “Something is still driving it. Saying it’s triple negative is just a way of saying we don’t know what the driver is yet.”
When scientists discover a cancer’s addiction—how it drives its growth—doctors can target it. This is the model of the partnership between Richer and Anthony Elias, MD, breast cancer program director at CU Cancer Center. Richer’s lab uses cell culture and mouse models to discover and validate breast cancer targets and treatments. Elias incorporates those findings into clinical trials with his patients.
The pair has been leading the national charge toward proving a new driver and target in breast cancer: androgen. It turns out, in many women’s breast cancers live cells that act like Conan the Barbarian. These cells have learned to drive their growth with androgen receptors. Thus, when they grab testosterone or other even more potent metabolites of testosterone, they grow like Schwarzenegger’s muscles.
Overall, 77 percent of all breast cancer cells are androgen receptor (AR) positive. And, “even 10-25 percent of triple negative breast cancers continue to express AR,” Richer says. This means that up to 25 percent of these hardest-to-treat breast cancers could be susceptible to treatments that block cells’ androgen signaling ability–like the treatments currently in use with prostate cancer.
Richer and Elias recently started a first-of-its-kind, phase I clinical trial at CU Cancer Center using the anti-androgen drug enzalutamide (approved for prostate cancer use), with advanced breast cancer patients who haven’t responded to existing therapies (clinicaltrials.gov identifier NCT01597193).
“This work is a concise example of modern cancer science in action,” Elias says. “We noticed something in the clinic, namely that AR was high in breast cancers resistant to anti-estrogen therapies; worked on it in the lab, and now are happy to report the lab work is once again back in the clinic where it has the very real potential to benefit patients.”
The drug works in an interesting way: Instead of stopping the body’s production of testosterone (e.g. Lupron), or blocking cells’ androgen receptors (e.g. Casodex), enzalutamide works by keeping androgen receptors from pulling their payloads inside the cell’s nucleus.
“Normally, the way these hormones work is by attaching to receptors in the cell cytoplasm, at which point the receptor draws itself and the hormone molecule inside the nucleus where it regulates genes,” Richer says. The genes regulated by these hormones tell breast cancer cells to survive and reproduce beyond control. Enzalutamide makes androgen receptors unable to go into a cell’s nucleus—and so the message of uncontrolled growth never gets delivered.
Richer and Elias suggest that, serendipitously, the inability of breast cancer cells to pull androgen inside their nuclei may stop them from driving their growth with estrogen signaling as well. “We’ve seen that something in this estrogen growth signaling also depends on the presence of androgen receptors,” Richer says.
In their preclinical work, the anti-androgen drug enzalutamide was as effective as the anti-estrogen drug tamoxifen in reducing tumor growth in preclinical models of breast cancers that have both androgen and estrogen receptors.
If this sounds like a great leap forward in the way the world treats breast cancer, that’s because it certainly may be. Richer and Elias recently earned a major grant from the U.S. Department of Defense Breast Cancer Research Program to continue their interplay of lab and clinical work that could solidify anti-androgen therapies as common arrows in the quiver of breast cancer care.
“Sure, cancer cells continue to mutate. You put selective pressure in one place and they can mutate to a different dependence,” Richer says. “What we’re hoping is that when we combine anti-androgen therapy with something like the anti-estrogen tamoxifen or aromatase inhibitors, it may kill enough of the cells that they won’t be able to mutate fast enough to keep pace—that they won’t be able to come back.”
Soon breast cancer doctors may target the disease with a prostate cancer drug. But the list of cancers that may benefit from anti-androgen therapies doesn’t end with two.
Androgen Receptors in Bladder Cancer
Now you know many ways to break the chain of androgen dependent growth signaling: by stopping hormone production, by blocking the attachment of hormone to receptor, or by keeping the receptor from pulling its payload inside the cell nucleus.
Similarly, there are many links in the chain that connects the occurrence of cancer to a fatal outcome. For example, a cell can mutate into cancer but if a tumor can’t grow the new blood vessels it needs to supply itself with nutrients, the cancerous cell can’t make a mass. This link in the cancer chain is targeted by anti-angiogenesis drugs. Likewise, cancer cells depend on rushing through the cell cycle, crashing through gates that limit the growth of healthy cells—chemotherapy sits at these checkpoints killing the fast-dividing gate crashers.
Basically, by looking at the lifecycle of cancer cells or at the progression of the entire tumor ecosystem, researchers can discover these bottlenecks through which cancer must travel in order to be deadly. Plug one of these bottlenecks and cancer can’t reach its endpoint.
As you might guess, one of the most important hoops cancer jumps through on this path is metastasis. That’s because many cancers don’t kill at their sites of origin. For example, nobody dies of localized prostate cancer. It’s only when the cancer metastasizes to bones, lymph nodes, lungs, liver or brain that the disease turns deadly. Likewise, bladder cancer doesn’t kill in the bladder and if it would stay put, the disease would be largely manageable.
Staying put is the default of healthy epithelial cells—the ones that when mutated generally give rise to bladder cancer. These healthy cells must attach and stay attached to their surroundings—cells that accidentally break free know they’ve come unmoored and generally die of the programmed cell death known as annoikis. Bladder cancer that metastasizes has learned to evade this control.
CU Cancer Center researchers in the Theodorescu Lab have been at the forefront of work showing that a major mechanism that bladder and many other cancers use to attach at new sites of metastasis is over-expressing a protein called CD24. Think of it like growth-promoting glue. A bladder cancer cell mutates in a way that ramps up production of CD24. Then when it floats through the bloodstream, it uses this protein to glue itself to new sites and to stimulate its growth at the metastatic site such as the liver or bones. Sure enough, Theodorescu has shown that bladder tumors with higher levels of CD24 have poorer prognoses.
What leads to the over-production of CD24? If you guessed androgen, you’re right.
In a major paper published in the Proceedings of the National Academy of Sciences, Theodorescu showed that mice whose tumors had higher CD24 did worse—especially the male mice. Likewise, it was male bladder cancer tumors that carried poor prognosis along with high CD24.
“More than three times as many men than women are diagnosed with bladder cancer,” Theodorescu says. “To us, these sex-specific findings implied androgen involvement.”
Like Richer and Elias’ work with androgen in breast cancer, the story of androgen in bladder cancer has gone from clinical observation to the lab and should soon make its way back to the clinic. Theodorescu showed that androgen directly regulates CD24, which in turn, is an important driver of bladder cancer metastasis.
Now, “to me, it’s not a question of whether we should be testing anti-androgen drugs in bladder cancer patients, but in what settings,” Theodorescu says. “For example, when you look for androgen receptors in bladder cancer, a third of the cancers light up, a third if you squint the right way you can convince yourself they light up, and a third don’t express the androgen receptors at all.”
“Fundamentally the question I’m struggling with is how much androgen does a bladder cancer need in order to grow and hurt the patient?” Theodorescu says. “How many receptors make drugging with anti-androgens worthwhile?”
With prostate cancer, anti-androgen therapy is part of the standard of care. With breast cancer, it’s pushing toward the standard. And in bladder cancer, anti-androgen therapy is just now exploring its first foray away from the lab and into patients.
Soon, though, with a target in sight and good drugs already in hand, the same knob that Arnold turned up to signal the growth of his muscles, doctors may be able to turn down or stop the growth of many cancers.