About one out of every two people in the United States will find themselves in the path of this invading army at some point in their lives. Cancer is the second leading cause of death in the United States in all age groups. And despite decades of research and breakthroughs, many types of this disease are still deadly.
One particular type of renegade cell is breast cancer. Among women it is second in deadly force only to lung cancer. One reason: Breast cancer has the tendency to invade the brain. And lately, it’s been spreading there more often.
Yet breast cancer survival rates are rising, lifespans and quality of life after the disease are increasing and new treatments are evolving almost every day. That’s why brain metastases of breast cancer have been called the final frontier in this fight. If we can beat back this wave, we might just put breast cancer on the rails.
Discovering how to block this cancer’s path into the brain has become priority No. 1 for many in the field, including one WVU scientist, Paul Lockman, who’s taking a unique approach — one that involves deadly mice, complex math and a mysterious structure known as the blood-brain barrier.
But to understand the big questions he’s trying to answer, and what’s at stake, we have to talk to a couple of WVU doctors on the front lines of the struggle.
Like so many supervillains, breast cancer’s complex true identity is hidden under a cloak of mystery and misinformation.
It’s not unbeatable. For many cases of non-invasive breast cancer, survival rates can be 95 to 98 percent. When breast cancer is invasive, survival rates vary widely based on tumor size, whether it has spread to the lymph nodes and whether it has invaded other areas of the body.
“We don’t use the word ‘cure,’ because it’s not that predictable a disease,” says Dr. Geraldine Jacobson, radiation oncologist, professor and chair of the WVU Department of Radiation Oncology. “But for all intents and purposes, many women who are diagnosed with breast cancer are cured and many, whether or not they have a cure, are going to live for decades after diagnosis.”
Dr. Hannah Hazard, director of Clinical Services and surgeon-in-chief at WVU, helps patients differentiate breast cancer types with a plumbing analogy. If the ductile structures of the breast were the piping in your house, a non-invasive cancer would be stuck, essentially, in your pipes.
“This is why we do mammography, so that we can catch these cancers early,” says Hazard, MD ’01.
Indeed, early detection is a big factor in why death rates from breast cancer have been dropping since about 1989, especially among women under age 50.
Once the cancer figures out how to get outside the pipes, however, it becomes a different beast — spreading into surrounding tissue where it can use blood vessels and lymphatic channels like expressways to other areas of the body. This is called metastasis. Breast cancer’s favored sites to travel to include the bones, lungs and brain.
“The fact that more breast cancer patients are developing metastases is actually the result of a good thing. We are treating breast cancer patients better, they live longer, which means they can be at risk later on,” Jacobson said. After breast cancer becomes invasive, survival rates vary widely. Everything from the size of the tumor to the tumor cells’ genetic makeup and hormonal markers become essential factors in determining treatment.
“We are now able to directly target certain aggressive breast cancers with treatments specific to those types and as a result those patients can live a long time. Those patients, however, tend to be more at risk for brain metastasis,” Jacobson said.
Patients who have certain rare molecular or genetic markers, as well as young patients, tend to develop metastases.
“This is often because they tend to have a more virulent cancer. That’s the biggest subgroup of patients with brain metastases,” Hazard said. “If you have metastases to the brain, that is a more significant hit. Those tend to be more aggressive tumors."
Once the cancer has invaded the brain, oncologists like Jacobson and the team at WVU use the latest and most advanced tools to fight it and give the patient the best quality of life possible. Their battery includes tools like the gamma knife, a type of focal radiation that zeroes in on the cancer alone — so the rest of the brain doesn’t have to suffer through radiation — as well a procedure called hippocampal sparing, a national clinical trial technique that treats the entire brain with radiation while sparing the hippocampus — the part of the brain involved in learning and creating new memories.
These treatments have increased survival times and quality of life, but cancer marches on. With treatment, median survival is one or two years.
“We don’t yet have that magic bullet,” Jacobson says.
And no one has yet addressed some of the most fundamental questions about these cancers, questions that, if answered, would fundamentally change the way doctors treat cancer and, maybe, halt its spread.
“We need to know what, on the microscopic level, is happening when the cancer metastasizes to the brain,” Hazard said. “Why is it doing what it’s doing? What makes it do it? And how do we stop it?"
This is where Lockman comes in.
A NEW HOPE
Paul Lockman isn’t a medical doctor. He’ll be the first to tell you that. Although he trained as a nurse and spent years working in neonatal intensive care, he considers himself a scientist first and foremost. With a PhD in pharmaceutical sciences and an aptitude for complex math, he spent his time in graduate school studying how drugs move through the brain, not cancer.
However, it wasn’t long after he became an assistant professor that he was approached by the National Institutes of Health — about working on cancer. It turns out his way of using math to track the movement of substances through the brain could shed new light on a few of those unanswered questions.
Together with some of the world’s renowned experts on the disease, Lockman helped secure a $17 million grant to study brain metastases of breast cancer. Their biggest question: Why do otherwise effective cancer treatments lose their power in the brain?
One theory was that it all had to do with one of our bodies’ most vital security systems, a wall between the brain and the body called the blood-brain barrier. To understand this, think about the house analogy again, only imagine the mass of drywall, pipes, wires and insulation in the walls of a really well-built house, one with zero heat loss, zero energy loss, zero dripping pipes. This is like the structure of the brain. It is so tightly woven, almost nothing can get in — unless the brain wants it to.
“The brain is an incredibly dense organ in terms of its vasculature,” Lockman said. “If I was to take the capillaries out of your head and lay them end to end, it’s almost four miles in length.”
These capillaries are what feed the neurons in your brain. And your neurons are what make every thought, including the one you had just now, possible. There are about 100 billion cells and 8 billion neurons in your brain. And for every neuron, scientists believe there are two capillaries that support it and feed it energy in the form of glucose.
“Say I was to tell you to think about your big toe,” Lockman said. “Now, a small part of your brain just lit up. That entire process required glucose. So not only did your neuron fire when you thought about your big toe, but that neuron also sent a signal to its blood vessel to give it some glucose.”
But it isn’t just the brain’s density that protects it. Inside each capillary, where the blood and plasma flow, is a little junction, like a lock, made up of tightly knit proteins. These are designed to keep pretty much everything that could potentially be toxic for the brain out, from the naturally occurring toxins in plants that we eat to the drugs we take. Even the glucose the brain needs has to go through TSA-style security checks. The blood-brain barrier sends out its own bodyguard-like transport proteins to personally escort the glucose in.
“And many of our chemotherapy drugs are derived from plants,” Lockman said. That was the basis for the theory that the blood-brain barrier was responsible for blocking the effectiveness of cancer drugs moving into the brain.
To test this theory, Lockman first had to develop a better way to model what was happening.
“Everything we do is in a model,” he said. “You can do tests in a Petri dish, you can do tests in a computer, you can do tests with animals. We needed to have a model that was more like real brain metastases.”
In the old models, scientists would inject a mouse brain with cancer cells and call it a brain tumor.
“But I’m pretty sure that’s not how cancer cells get into the brain. We know it has to break up somehow and get into the blood and then it somehow gets into the brain,” he said. And they needed to see how that happened.
Unfortunately, the best way to create this new model would be to use mice.
And after years of working with them, Lockman had developed a deadly allergy to rodents. “I started having to wear gloves and a respirator all the time,” he said. “But we got it done.”
‘THEN I WIN’
Thanks to some altered cancer cells, ones designed in a lab to go directly to the brain and live there, Lockman and his team were able to create new, more accurate mouse models, which later helped them show that while the latest cancer treatments were making it into the brain in small amounts, the blood-brain barrier was blocking them too much to be effective.
This was a huge step forward. But it hadn’t answered one of the even bigger questions of the field, one that had plagued Lockman since he started working on cancer.
"We know breast cancer cells can get into the brain, but how they get into the brain — no one knows,” he said. “Cancer cells are the size of a small house compared to a drug molecule that might be the size of a pen. So how does this massive cell get through the blood-brain barrier and the tiny drug molecule doesn't?"
In order for a cancer cell to cross from inside the body to inside the brain, they have to somehow trick the body’s defenses into letting them in. Lockman theorized that the weak spot in the brain’s defenses might have to do with those junctions that allow glucose into the brain.
“The first thing I had to do was figure out a way to measure how many tumor cells were getting across,” he said. “So we made the cancer cells super-super-fluorescent using jellyfish genes, then we injected them into the mouse brains.”
A week or so later, they stopped the experiment to see where the cells had ended up. At that point, some of the cells had already crossed into the blood vessels and some were still outside. That meant the process wasn’t automatic. Each cancer cell had to have some sort of key to open the security wall, and since those junctions were made of proteins, Lockman theorized the key might also be a protein.
“One of the things we did then was to block an inflammatory protein called TGF-β1, or TGF Beta. We know that TGF Beta was partly responsible for the cancer cells getting out of the breast; we know this inflammatory protein is involved when they start to go all over. So we thought maybe it’s also involved when the cells get into the brain.”
Lockman first tried blocking that protein in the cancer cells themselves. He then repeated the experiment and, after a week, looked under the microscope again and finally saw something like a breakthrough.
“The number of cells that had gotten into the brain was down by half,” he said.
But half is still too many. So he tried blocking that same protein in both the cancer cells and the animal itself.
After a week, 80 percent of the cancer cells were kept out of the brain.
The implications of Lockman’s findings could be monumental for the fight against brain metastases of breast cancer — arguably the most virulent and deadly form of the disease. His plan? Rather than fight to get drugs into the brain, use the body’s own security system to keep the cancer cells out.
“If we can continue on this path, what we’d really like to do is stop the cancer cells from getting into the brain altogether,” Lockman said. “Because then I win. If I can keep the cancer cells from ever getting into the brain, we can treat it. We can stop the whole process. We can beat it.”
'ONCE MORE UNTO THE BREACH'
Like any weapon, Lockman’s findings are not the magic bullet we might hope for — yet. But for some who will be diagnosed with breast cancer in the future, it may offer hope that though they have this terrible foe to fight, it will never reach the brain. “It won’t work for every breast cancer patient,” he said. “But there is a certain subset of patients who are identified who are at really high risk for brain metastasis. If we can start these therapies with those who are at high risk, we might be able to prevent it. But there’s a lot of work still to be done.”
Today his theories are already being put the test. With his more accurate mice models as the foundation, a new drug to block tumor cells from getting into the brain has been tested, and the findings published — with more on the way.
On the front lines, Hazard, Jacobson and the breast cancer team at WVU are still deep in the fight, but findings like Lockman’s offer new tools and new hope for doctors and patients alike.
“Hopefully someday my job will be obsolete,” Hazard said. “Which is perfectly fine with me.”