Can Cancer Killers Get Past the Brain's Bouncers?
By Lina Zeldovich
- Melanoma, lung and breast cancer have a particular penchant for spreading to the brain. But a special membrane known as the blood-brain barrier makes it hard for cancer drugs to reach tumors that have metastasized to the brain.
- While there are a few available medicines that have been specifically developed to address brain metastases, scientists are now developing innovative new therapies that are intended to get past the blood-brain barrier, stay inside and more effectively kill cancer that has metastasized to the brain.
Over the past decade, scientists have made great strides in the fight against cancer. Even with some of the harder-to-beat cancers, certain therapies can keep tumors in check, buying patients more time. Yet, paradoxically, as therapies become more effective and patients live longer, the chances of cancer cells eventually finding their way into the brain also increase.
Several types of malignancies, including melanoma, lung and breast cancer, have a particular penchant for spreading to the brain — between 10 and 30 percent of patients develop such metastases. Other tumors, such as glioblastoma, originate in the brain and metastasize throughout it. However, there are very few therapies available that are specifically engineered to address brain metastases.
There are two hurdles to overcome when crossing the blood-brain barrier: getting in and staying in.
Nick Saccomano, chief scientific officer at Pfizer Boulder Research and Development
Once cancers take hold in the brain, they become difficult to reach for many existing medicines, says Nick Saccomano, chief scientific officer at Pfizer Boulder Research and Development, which focuses primarily on the discovery and development of oncology therapeutics. That’s because the brain is separated from the rest of the body by a blood-brain barrier, a special membrane that normally prevents microbes, viruses, toxic chemicals and other harmful compounds from getting into the central nervous system, which consists of the brain and the spinal cord. Only certain molecules such as iron and glucose are “escorted” in by a special protein called transferrin, while all others are actively transported out. For a therapeutic molecule, reaching the brain is like being admitted to an elite social gathering. You need an escort to enter, but “bouncers” could still kick you out.
“There are special transporter molecules that transport the unwanted substances out of the brain,” explains Saccomano. “There are two hurdles to overcome when crossing the blood-brain barrier: getting in and staying in.” These hurdles are even harder for cancer drugs to overcome, he adds, because their structures make it difficult to not only get into the brain, but once in, to avoid being transported back out. Because of this, the efficacy of most current cancer therapies in treating brain metastasis is limited by poor brain penetrance.
That’s why researchers are designing next-generation therapies with the intent that they will cross the blood-brain barrier, stay there and more effectively treat cancer that has spread to the brain. Central to those efforts is the need to identify the necessary qualities and attributes therapeutic molecules must have in order to reach the brain, and stay there, in sufficient concentrations.
“We now include brain-penetration qualities into our minimal design,” Saccomano explains. He likens it to carefully designing a car before starting to build it.
These next-generation therapies currently in development include biomarker-driven drugs that are designed to target specific gene mutations that can lead to cancer cell growth, including growth in the brain. “At Pfizer Boulder, we are working to develop several potentially first- and best-in-class therapies that not only target gene mutations that commonly appear in cancer patients … but also have the ability to cross the blood-brain barrier and treat cancer that has spread to the brain and central nervous system,” says Saccomano. His team is currently working to develop several potentially brain-penetrant molecules that target different gene mutations.
Together, these difficult to treat types of cancer affect tens of thousands of patients every year who could benefit from brain-penetrant therapies, Saccomano adds. “Drugs that can cross the blood-brain barrier have huge potential benefits for patients.”
Scientists are attempting other approaches too. Susan Rosenbaum, founder and CEO of Lauren Sciences, is using a patented nanovesicle technology that aims to deliver existing FDA-approved cancer drugs through the blood-brain barrier. These compounds have been able to deliver and release drugs into tumors in mice, and the company is working toward human clinical trials.
James Gorman at Harvard University’s Wyss Institute for Biologically Inspired Engineering is using yet another tactic. His team is devising molecular “shuttles” that would attach to iron molecules — and hitchhike their way into the brain. While their research is in the early stages, their technology mimics the biochemistry of the blood-brain barrier, allowing them to test the shuttles’ efficiency and improve their quality.
“We isolate our own molecules that specifically bind to the proteins that transport iron,” Gorman says. If they work, the shuttles could potentially carry therapeutic compounds across the blood-brain barrier, which also holds promise for treating neurodegenerative diseases, another pressing societal burden. Gorman notes that the last Alzheimer’s drug was approved in 2003 because many have failed to reach the brain in sufficient concentrations.
“That’s long been the challenge for cancer drugs too,” says Saccomano. Science can throw up fresh stumbling blocks, but the trend is clear: Using varied approaches, researchers are striving to develop a new generation of therapeutic solutions that might safely penetrate the blood-brain barrier. “Scientists,” Saccomano says, “should be looking at this from all angles.” Diverse strategies mean the chances of success are higher and cancer drugs might soon make it to the brain’s select guest list.
- Lina Zeldovich, OZY Author Contact Lina Zeldovich