The most deadly prostate cancers are addicted to SRCs. They’re like crack for cancer. But guess what? “SRCS can be reprogrammed. They can be suppressed.”
How do you stop a runaway train? Take a few seconds and think about it; feel free to draw from any runaway-themed movies you might have seen.
Well, you could go after the track: rip it up: a train can’t roll for long just on plain old ground. Get rid of its fuel: this was an idea in “Air Force One,” where Harrison Ford dumped jet fuel in mid-air. Slow it down: in “Unstoppable,” Denzel Washington and Chris Pine tried to halt a runaway by pulling it from behind with another engine. This actually didn’t work for very long; next, they tried to engage the brakes – first on the individual cars, and then on the main engine. Blow it up: If you didn’t really care about innocent bystanders or collateral damage, you could just take a rocket-powered grenade or heat-seeking missile and try to destroy the runaway engine… if you happened to have such a weapon, if you knew how to use it – and if, of course, this weapon actually works like you hope it will.
Metastatic prostate cancer is like a runaway train. Every day, our PCF-funded scientists are getting closer to stopping it, with a drug or treatment that targets one of cancer’s weak spots. Cut off its fuel: Well, that would be ADT (androgen deprivation therapy), shutting down testosterone and other androgens, or male hormones; and also androgen receptor-blockers, drugs like abiraterone, enzalutamide, and apalutamide. Hinder its ability to grow: chemotherapy, of course, and drugs that target angiogenesis – like the tracks for the train, there are pathways cancer needs before it can get rolling. But these types of drugs don’t often work for very long.
Wouldn’t it be nice to target several of these ideas at once? Not an either-or situation, but a “this mechanism and this one, too, and also this one.”
We may have found one. It’s preliminary, and probably two years away from clinical trials, but PCF-funded investigators Salma Kaochar, Ph.D., Nicholas Mitsiades, M.D., Ph.D., and colleagues at Baylor College of Medicine seem to have found a promising new strategy that rips up the track, and dumps the jet fuel, and turns on the brakes – and causes, at least in mice, no collateral damage.
It shortstops prostate cancer at the protein level and at the same time, turns up the immune system – in a way unlike any form of immunotherapy currently available.
“We are developing a first-in-field approach to target the previously undruggable family of cancer-promoting genes for the treatment of both androgen receptor-dependent and androgen receptor-independent castrate-resistant prostate cancer (CRPC),” says Kaochar. She presented her findings at the 2018 Scientific Retreat of the Prostate Cancer Foundation.
What is this secret weapon, and how does it work? If we continue with our movie analogies – and pardon us for doing so, but otherwise this stuff is hard to explain – then it’s not so much like finding that one tiny weak spot that Luke Skywalker managed to hit on the Death Star in the very first “Star Wars” movie (episode IV). No, it’s more like that scene in “Raiders of the Lost Ark,” where Indiana Jones, faced with a fearsome, sword-wielding assailant, doesn’t try to fight by that guy’s rules, with another sword or his bullwhip. Instead, he pulls out a pistol and shoots him. He changes the game. Alexander the Great did the same thing 2300 years ago, when faced with the Gordian Knot – a puzzle no one could untangle. He sliced it apart with his sword.
Kaochar and colleagues have found a target that no one has ever tried in cancer before: p160 SRCs, or “steroid receptor coactivators.” These are “master regulators of transcription factor (key proteins) activity necessary for cancer cell proliferation, survival, metabolism, cell motility, invasion and metastasis,” she explains. “In prostate cancer, they are required for the function of the androgen receptor and its variants.”
Transcription factors are proteins that act as a key to turn on a gene – just like a key in the ignition of a car. Except here, if you have more keys, you can make the engine go faster. “In CRPC, there is frequent overactivation of p160 SRCs,” Kaochar continues. “This results in increased androgen receptor activity, faster growth of the prostate cancer cell (more powerful and determined cancer cells), resistance to therapy, and bad outcomes. Increased levels of these SRCs are associated with very poor prognosis. SRCs are also important for the energy homeostasis (energy balance) in prostate cancer.”
The most deadly prostate cancers are addicted to SRCs. They’re like crack for cancer.
But guess what? “SRCs can be reprogrammed. They can be suppressed.” And this can happen in focal, localized tumors as well as in metastatic cancer. Theoretically, there is no point in cancer at which this couldn’t start to work. “Our goal is to find something to hit cancer at that late stage, where there’s absolutely no other treatment, where it’s all over, everywhere.”
In preclinical experiments – limited so far to mice– Kaochar and colleagues are using “pulses” of treatment, not one continuous treatment. Each pulse shuts down all the machinery cancer needs to grow, and also energizes the body’s immune system to fight the cancer – thus hitting cancer from multiple sides.
Overactivation of SRCs appears to be extremely common in prostate cancer, and in other forms of cancer, as well. So far, in laboratory tests using various types of aggressive, hormone- and chemotherapy-resistant prostate cancer cells (because men with prostate cancer don’t all have the same genetic mutations), 100 percent of prostate cancer cell lines tested in a dish have tested positive (see side story) as being driven by SRC.
This is the latest exciting chapter in work that began in 2012, with a Movember-PCF Challenge Grant to Kaochar’s mentor, legendary Baylor molecular and cell biologist Bert O’Malley, M.D., known as the “Father of Molecular Endocrinology.” O’Malley discovered the first co-regulator, SRC1, in 1991. “Before his discovery, this entire field did not exist,” says Kaochar. “He spent the last 30 years really working to understand the biology of these co-regulators.” O’Malley’s major research interest was in breast cancer; Kaochar, who was in industry, at Roche Pharmaceutical Company, came to Baylor in 2015 as a research fellow in oncology. She began driving the preclinical work on SRCs in prostate cancer, in collaboration with Nicholas Mitsiades, and soon joined the faculty as an assistant professor. “These p160 SRC molecules are important in many cancers,” Kaochar says, “including uveal melanoma,” a particularly nasty form of melanoma that attacks the eye. “Uveal melanoma is a hormone-independent cancer, and it is heavily addicted to these molecules.” Not only is uveal melanoma deadly; it is an “orphan disease.” There is no version of the PCF – no foundation to fund critical research like this – for uveal melanoma; it’s too rare. But what this PCF-funded research is uncovering may lead to the first effective treatment for this disease, too.
Kaochar left industry because, “in a way, your hands are tied; the research in industry is very much market- and money-driven,” she says. “But in academic science, you can truly be creative, think outside the box, and take worthwhile risk – and that’s the only way you’re going to cure this disease, is by not going with the flow.” Inspired by mentors and colleagues at Baylor and fellow PCF-funded investigators, Kaochar says she feels like she’s “at the edge of the world. Every day we are learning something totally new about the intricacies of the cell—how it functions, grows, evolves. To be able to decipher this puzzle and convey to other scientists and the public, ‘This is how the cancer cell is working,’ is incredible. I’m not interested in discovery for the sake of discovery; I want my work to mean something, to help patients we couldn’t help before.”
This work would not have been possible without the PCF, and particularly, without the support of the Barry Family, who funded her Young Investigator Award. “The generosity of this family has allowed us to carry out cutting-edge preclinical development work,” which has “helped prepare us for a large National Cancer Institute Moonshot grant.” Because of their PCF-funded work, Kaochar and colleagues received funding from the National Cancer Institute’s Moonshot Program to develop novel prostate cancer preclinical models. Baylor is one of only six centers in the country to receive this funding, and the only center focused on prostate cancer.
“For three decades, Baylor has done some of the most important basic research on how these factors work,” says medical oncologist and molecular biologist Jonathan Simons, M.D., CEO of the PCF. “Baylor scientists have relentlessly studied hormone receptors and transcription factors, and now they have identified a new drug target and are moving the testing along. This is very exciting science.”