The challenge of finding new tools to fight prostate cancer

The challenge of finding new tools to fight prostate cancer
Aurich Lawson | Getty Images
In the US, September is National Prostate Cancer Awareness Month. This feature highlights why catching prostate cancer early can be critical, and what researchers are doing to improve the odds of controlling the disease once it’s found.

Prostate cancer is a paradox. It has one of the highest early-stage survival rates of any cancer, yet it’s the second most common cause of cancer death in the US among people with a prostate (behind only lung cancer). Localized prostate cancer, only found in the organ itself, is highly curable. But once it becomes metastatic, spreading beyond the prostate, it is incurable and leads to death.

This makes studying it complicated. How do you understand something that is at once easy and impossible to cure? Researchers tackling the paradox are harnessing technologies like imaging, genetic sequencing, big data, and artificial intelligence to work toward changing outcomes for patients across the spectrum of cancer severity. From understanding what makes the cancer develop in the first place to identifying new drugs and new methods of treatment—each innovation is an opportunity to save lives. Here’s a look at just a few of the countless projects in progress around the world that could one day change the treatment landscape for prostate cancer.

Quantifying the paradox

The 10-year life expectancy for localized prostate cancer is around 98 percent. It’s remarkably curable. Many prostate tumors are so slow-growing and nonthreatening, they’re not even treated—they’re simply monitored to make sure they stay nonthreatening. “You’re more likely to die with prostate cancer than of prostate cancer,” says Dr. Isla Garraway, director of research in the Department of Urology at the University of California, Los Angeles (UCLA).

But once the cancer becomes metastatic, that prognosis changes completely. Treatments can improve a patient’s quality of life and increase their lifespan, but eventually the cancer will become resistant to all treatments and turn fatal. According to Dr. Yaw Nyame, an attending physician and assistant professor of urology at the University of Washington: “For most [prostate] cancers, when you are diagnosed because you have symptoms it’s oftentimes a sign that your disease is really advanced. If you have pain, or blood in the urine, or difficulty emptying your bladder, it’s likely you have advanced cancers.” In other words, the danger is compounded by the fact that there are no symptoms until it’s too late to cure.

Finding prostate cancer before it becomes metastatic is critical for managing the disease.
Enlarge / Finding prostate cancer before it becomes metastatic is critical for managing the disease.

Meanwhile, the prevalence of the disease is staggering. About 1 in 8 people with a prostate (depending on who you ask) will be diagnosed in their lifetime. So far in 2021, the US has seen roughly 248,530 new cases and about 34,130 deaths.

Estimates of the percentage of metastatic cancers run from 5 to 10 percent, but the huge number of overall cases means that even the low-end estimate will ultimately mean a lot of cancer that resists treatment. And the CDC says the percentage is on the rise, which means it’s more important than ever for science to solve the problem of incurable metastatic prostate cancer.

Understanding the underlying causes

“For cancer researchers in general, we’re always seeking out the origins. Where does it start, what cells does it start in, how is it co-opting the processes of normal cells to evade the immune system or invade areas where it shouldn’t be?” says UCLA’s Dr. Garraway. “Just like other cancers, the whole idea is to understand the biology of the prostate tumors better so you can find the Achilles heel of that tumor.”

The challenge, Garraway tells Ars, is that for a long time, research into what causes prostate cancer growth was focused on the indolent (or slow-moving) versions of the disease that were curable. More surgeries removed slow-growing tumors, leaving researchers with more access to these tissue samples. Metastatic patients were less likely to undergo surgery because their cancers had spread to other parts of their body, so those samples were studied less often.

“For those 10 percent or so who are destined to have this metastatic disease, at least half of them already had spreading of their cancer at diagnosis,” she says. “They weren’t surgical candidates, so we weren’t capturing their tissues. And it’s a challenge to get enough tissue from a metastatic lesion.”

Recent advances in technology have changed that reality. Over the past decade, Garraway says next-gen genome sequencing technology has allowed scientists to classify and analyze minuscule amounts of tissue. Doctors can now use a small needle to collect “a very tiny little piece of tissue,” creating a paradigm shift in the study of lethal prostate cancer.

A look at prostate stem cells

It’s now possible to ask whether there are factors that mark high-risk tumors early on. Garraway compares these tiny samples of metastatic tumor cells to non-cancerous prostate tissue, hoping they can provide a clue as to the cause of the former’s aggressive behavior.

She does this by focusing on the stem cells normally found in the prostate, which can generate any cell type in this tissue (though, unlike embryonic stem cells, they can’t generate any other tissues). But stem cells show up in prostate tumors, too. Garraway hypothesizes that these prostate-specific stem cells might have features that make tumors more dangerous. Comparing the genes that are active in both prostate stem cells and cancers “gave us ideas about how these more aggressive cancers are co-opting benign stem cell traits. The stem cell’s primitive embryonic-type properties can facilitate infestation and spreading,” she says.

Because prostate stem cells can generate new glands, they’re really good at moving around and invading other parts of the body. “And they’re more hardy. They can survive things differentiated cells can’t survive,” Garraway says. “They’re resistant to radiation and chemotherapy, and they can survive damage to their DNA. We think activating these survival mechanisms supports tumor initiation.”

A prostate tumor, with green and red labels identifying the presence of proteins found in stem cells.
A prostate tumor, with green and red labels identifying the presence of proteins found in stem cells.

Garraway and her collaborators took healthy prostate tissue samples, sorting the cells by the different proteins they make, and identified if the cells have traits like the ability to regenerate prostate tissue. The results were compared to ones generated using the stem cells found in the metastatic tumor samples. “This is where it gets interesting,” says Garraway. It turned out that both benign tissue and the tumor cells expressed a protein called Keratin 13. That protein was very rare in most healthy tissues, but, ”we almost always saw [it] in biopsies that had metastatic disease,” she says.

Before this, the researchers thought Keratin 13 was what Garraway called a “run of the mill” protein that simply helped give a cell shape and stiffness. But they knew some keratins can also play a role in the signaling needed when cells migrate. “So now what we’re focused on is what it can do,” Garraway tells Ars. They’ve started by removing Keratin 13, which results in incapacitating the cells. “We were surprised cells that express Keratin 13 can no longer metastasize. It suggests it has a functional role in the metastatic process.”

This research is still in the very early stages. Garraway calls it “an example of how research and discovery is done, but it shouldn’t be considered a potential new therapy for now.”

Even if it doesn’t lead to treatments, the research she and her colleagues are doing will still contribute to the overall science of prostate cancer. “Our bigger focus is in understanding the tumor biology of these aggressive cells,” she tells Ars. “Prostate cancer that is metastatic is incurable. We have to understand who and why and how.”

Growing mini-prostates

As an alternative to tumor samples, Dr. Himisha Beltran, director of translational research within Medical Oncology at the Dana-Farber Cancer Institute, is using samples to build new cell lines. Cell lines are groups of genetically identical cells that grow well in culture, and they retain features of their source—in this case prostate cancer. They make studying that source much easier.

Through her work in the clinic, Beltran noticed that few prostate cancer cell lines existed, and they didn’t represent the types of tumors she was seeing in her patients. “Considering how prevalent prostate cancer is and all the varying aggressive types, it’s surprising we don’t have many cell line models,” she says. The lack of cell lines means that it’s difficult to understand what makes different prostate cancers grow or to experiment with targeted treatments.

Dr. Beltran specializes in precision medicine, and she can analyze the genome of her patients’ tumors. But she was frustrated that there was often no data available that indicated which treatments to use based on those genomes. This motivated her and her colleagues to start propagating new cell lines as a way of matching genomes with effective treatments.

To start finding matches with treatments, she grows mini-prostates, called organoids, in her lab. “We use the fresh tissue and grow them in the laboratory. We use a special media that promotes the growth of human cells, and they grow to three-dimensional structures,” she says. Organoids can also be implanted in mice to see how they change once they’re in a living system.

But the organoids often grow slowly—or not at all. “We can continue to develop them to try to expand the clinical relevance of our lab research and bring that information back to patients,” Beltran tells Ars. “It’s an important area, but it’s an area we could do better.”

Organoids are three dimensional tissues grown in culture that help us understand the development of normal tissues.
Enlarge / Organoids are three dimensional tissues grown in culture that help us understand the development of normal tissues.

There is, however, one category of prostate organoids that does very well: the ones grown from some metastatic tumor cells that display what’s called “lineage plasticity.” That means cells change their identity, turn off their prostate genes, and convert into non-prostate cells. Because of this, their growth is less driven by hormones, so the common testosterone-blocking drugs don’t work well against them.

Currently, only one cell line exists that allows us to study these unique prostate-derived tumor cells. So the fact that they grow into organoids is particularly useful. “We can rapidly manipulate them in the lab and do drug testing,” Beltran says. “We can also develop them in a mouse model to understand patterns. They go through the same changes in the mouse as they do in humans. We’ve shared them with other laboratories so they can develop mechanistic projects. We did drug screening, and we’re now using them to discover a new [drug] target.”

The job of making new cell lines that develop into organoids, she says, has been an “overwhelming challenge, but we’re excited about how much progress is being made. It’s not insurmountable.”

Discovering new RNA

Not all research into the causes of prostate cancer requires a laboratory; some is happening in computers. Dr. Paul Boutros, a data scientist and a professor of human genetics at the UCLA Jonsson Comprehensive Cancer Center, is using data collected from prostate cancer patients to analyze a poorly understood form of RNA found in prostate cancer called closed-loop RNA. Figuring out what, exactly, its purpose is might be a key to new kinds of treatments.

Most cancers happen due to mutations that result in altered proteins. But Boutros says that “prostate cancer is one of the most fundamental exceptions. There are actually few mutations in the genes that lead to [mutated] proteins. On the spectrum of human cancers, prostate is one of the most variable and has the fewest mutations. Which is kind of weird.” He and a few others started wondering whether mutations that drive prostate cancer alter RNAs instead of proteins. “Maybe in some fundamental way it’s becoming more aggressive when [an] RNA gets messed up,” he suggested.

Based on this speculation, Boutros decided to look at RNAs more closely. “We’ve found a lot of evidence that there are different types of RNA that don’t make protein, and we thought they were just noise,” he says. One particular form of RNA turned out to be an important driver of prostate cancer: it’s shaped in a closed loop instead of a linear strand. “They don’t look like anything else in the cell. We barely understand what they do,” he says. “But if we remove them the cancer stops growing. But they also exist in normal prostate cells. It might be an important part of nature we don’t understand.”

RNAs can form complicated structures thanks to internal base pairing. This makes understanding their function challenging.
Enlarge / RNAs can form complicated structures thanks to internal base pairing. This makes understanding their function challenging.

These closed-loop RNAs have been found in about five or six other forms of cancer, but they don’t show up in any kind of uniform amounts. Prostate cancers, however, seem to have more of these RNAs, and they seem to have the most impact there. (In healthy cells, they are very prevalent in the brain, Boutros says, which suggests they have an “unknown developmental mechanism important in normal tissues.”)

But we wouldn’t have known to look for them if it weren’t for computer analysis. “This is all about data. The way we found these wasn’t by developing some brand-new technology; it was developing new and improved algorithms to extract this information from data we have already collected,” he says. “We are trying to figure out what the heck these things do… If there’s 1,000 novel things we haven’t seen before maybe one is gonna be a really good [drug] target. We’re really excited about that possibility.”

Advancing prostate cancer diagnosis

Because prostate cancer doesn’t present symptoms until it’s advanced, it’s difficult to diagnose at early stages. For many years now, the gold standard of testing has been to have anyone at risk take what’s called a PSA test. This stands for Prostate Specific Antigen, and it’s a blood test that looks for proteins produced by the prostate cells, which are present in higher numbers when a person has cancer.

The PSA test is not without controversy. According to the University of Washington’s Nyame, because many forms of prostate cancer are so slow-growing, the PSA test detects cancers that don’t actually need to be treated. This can lead to overtreatment. “We all want to prevent men from dying from this disease, and we want to avoid harming men unnecessarily that may never be impacted by it,” says Nyame.

According to UCLA’s Garraway, “We can discover prostate cancer, but we don’t always need to treat it. Sometimes we can just put patients on surveillance protocols and monitor the tumor. Where the prostate is located in the pelvis and close to organs important for sexual, urinary, and bowel function—mucking around there can impact the quality of life. They can lose sexual function. We definitely want to be really careful in terms of not over-treating cancers.”

Some of this controversy has been addressed by reducing the number of people who take the test. Today, it’s limited to those between 55 and 74, as well as high-risk groups, such as those with prostate cancer in their family and Black men. Additionally, “we’ve seen a real growth in the use of MRI that can help us find clinically significant cancers that we want to detect,” Nyame says. But MRI is more expensive and involved than the PSA test. “I find it hard to believe we’ll be in a scenario where PSA isn’t the first test we get.”

Advances in imaging

The next big thing in diagnosing prostate cancer is using radioactive materials to directly label cancer cells, which lights them up when patients have a PET Scan. There are quite a few researchers working to perfect this technique and bring it to market—so many that it has become a bit of a prostate cancer “space race.”

Attaching small radioactive molecules (also known as tracers) to cancer cells isn’t a new idea. It has been done for years in a slew of cancers, including lung, colorectal, breast, ovarian cancer, and brain cancers. But nobody has been able to make it work in prostate cancer. For the successful tests, a radioactive atom is attached to glucose and injected into a patient. Fast-growing tumor cells love to eat sugar, and so they take up the radioactive glucose, and the PET scan can illuminate the cancer’s exact location.

But Michael Hofman, director of prostate cancer theranostics at the Peter MacCallum Cancer Center in Melbourne, Australia, notes that prostate cancer grows too slowly to take up enough sugar. It wasn’t until the discovery of the Prostate Specific Membrane Antigen (PSMA) that researchers were able to attach a radioactive material specifically to prostate cancer.

“If you look at a prostate cancer cell, there are receptors that sit on the top of the cell for signaling. [PSMA] is very specifically expressed just on prostate cancer cells,” Hofman says. “If we look at other types of tumors or normal tissues we don’t see PSMA. It’s a great target for imaging.”

Left three images: Ga-68 PSMA PET/CT scan showing spread of cancer to a bone and lymph node in the pelvis. Standard imaging (right two images) shows no indication of this cancer.
Enlarge / Left three images: Ga-68 PSMA PET/CT scan showing spread of cancer to a bone and lymph node in the pelvis. Standard imaging (right two images) shows no indication of this cancer.
Prof Michael Hofman, Peter MacCallum Cancer Centre, Melbourne, Australia.

Hofman’s lab linked a radioisotope called Gallium 68 to a short protein that sticks to PSMA. According to Hofman, “it’s injected into a vein intravenously and attaches to the prostate cancer cells no matter where they are. We can then see any prostate cancer anywhere in the body.” Clinical trials showed an enormous jump in our ability to display very small incidences of cancer throughout the body. The PSMA Gallium 68 PET Scan was approved by the FDA in December of 2020. The results, Hofman says, are “leading to adoption globally.”

Meanwhile, scientists around the world are working on their own versions of the PSMA tracer by attaching different types of radioisotopes. Hofman says any one of these could become the industry standard, but he notes that the Gallium 68 tracer is unpatented. “It’s good to have competition and choices for patients,” he says. And without a patent, the Gallium 68 is essentially open source.

Finding treatments from greater understanding

At every step along the way of building knowledge about the mechanisms and processes that drive prostate cancer, scientists are thinking about the end goal: development of new treatments and saving lives.

A whole series of methods are currently in use for treatment. According to UCLA’s Garraway, depriving the cancer cells of testosterone (through pharmaceutical or surgical castration) is often a successful means of killing them off. There are new drugs, she says, that either prevent cancer cells from taking up testosterone or block them from producing their own.

Immunotherapy is also an option, with treatments working like a vaccine, training the patient’s own white blood cells to attack prostate cancer cells in culture, then re-injecting them into the body. Other approaches to immunotherapies have been tried but have not been as successful so far.

Nearly all of the research mentioned in this story could eventually have some application in treatment. The PSMA Gallium 68 tracer was a breakthrough in diagnosis, but researchers are already working on evolving the technology in new directions. Dr. Robert Reiter, director of UCLA’s prostate cancer program, worked with Hofman to help develop the Gallium 68 tracer. He’s now developing different tracers to assist with surgeries. For example, one marks tumors so that they can be detected by a sound-emitting probe on the operating table. He’s also working on developing a method of attaching drugs to proteins that deliver them directly to cancer cells.

Hofman has modified his PSMA tracer by attaching more potent radioactive isotopes. “We inject it the same way; it travels around the bloodstream and gets taken up into cancer cells. It emits high-energy radiation that travels only 1mm and kills the cell. It’s a novel way to deliver high doses to the tumor, killing prostate cancer wherever it is,” he says. Trials in Australia were promising, and Novartis currently has the rights to produce it in the US.

Meanwhile, Dana-Farber’s Dr. Beltran is one of several researchers building precision medicine databases that will collect data from cancer patients and build genetic profiles of different types of prostate cancer. This will help doctors identify drugs approved for treating cancers with specific mutations that might be viable for treating others. “We’re checking for hundreds of genes at the same time,” she says, referring to her collaboration. “Can we now start to understand all these other genes—how they’re working and how patients respond? We work together to follow the natural history of these less common mutations that we don’t have drugs for yet.”

The broad scope of research

The advances listed here barely scratch the surface of the range of research focused on better understanding the causes of prostate cancer. Other ongoing studies include improving immunotherapy treatments, training artificial intelligence to recognize prostate cancer in diagnostic slides that could be missed by the human eye, and searching the gastrointestinal microbiome to see if microbes are playing a role in fostering the cancer’s growth. Scientists are also trying to understand the biological and non-biological mechanisms that put Black men at higher risk for developing the disease and using big data to look at other understudied populations to discover potential risks that institutional biases might have missed. They’re researching biomarkers to help improve early detection as well as discovering ways to improve the PSA test to prevent overtreatment. Many potential treatments and innovations have already moved into clinical trials.

While much of this work may take decades, new advances are finding their way to patients every year. And as each new discovery pushes treatment a step forward, another life is saved.

Erin Biba is a freelance journalist covering science and technology. Her work has appeared in Scientific American, National Geographic, BBC, and elsewhere. Find her on Twitter @erinbiba.

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