Sean Lawler, Breaking Barriers for Treating Brain Cancer
Fourth in a series of four profiles on the 2017 winners of the BWH Health & Technology Innovation Grants. Each winning team competed in a “Shark Tank”-style event and was selected for a $50,000 grant for basic/clinical/translational science-focused as well as commercialization-oriented research projects. These grants are supported by the Brigham Research Institute and the BWH Health & Technology Sub-Committee, which comprises friends of the Brigham from the philanthropic world.
Before he joined the Brigham, Sean Lawler, PhD, of the Department of Neurosurgery, started his career as a molecular biologist. During the 1990s, Lawler studied the basic molecular underpinnings of mammalian cell communication, and gradually became interested in how to apply this knowledge clinically.
“In the trajectory of my career, I started out as a very basic scientist interested in the meaning of life, DNA, how DNA works, and all of those kinds of questions as a young man. Then as my career evolved, I became much more aware of how biology can be applied to the treatment of human disease and have a real impact on patients,” said Lawler.
A post-doc in the Department of Neurosurgery at MGH ultimately cemented Lawler’s research interest in brain tumors. “Once I started to find out more about the patients and what a devastating diagnosis glioblastoma really is, the penny dropped for me. All the things I’d learned about cell signaling were very pertinent to this disease,” said Lawler. He then went on to start a new Brain Tumor Research Lab at the University of Leeds in the UK, before returning to Boston to work at BWH in 2013.
Glioblastoma is an aggressive brain tumor that can be removed from the brain surgically, but not even the best neurosurgeons can physically remove all the tumor cells without damaging important brain tissue. The remaining cells resist therapy and rapidly regrow. Lawler’s lab is pursing multiple strategies to target those leftover glioblastoma cells and prevent them from growing. Peptides, or short amino acid chains, can also target glioblastoma by binding to cell surface proteins only on glioblastoma cells, and not on normal healthy cells, to distinctly tag those tumors. Most recently, investigators are trying develop approaches to allow drugs to cross the blood-brain barrier, an arrangement of cells that tightly controls what gets in and out of the brain. Many cancer drugs work well outside the brain, but they can’t cross the blood-brain barrier. This presents a difficult challenge for researchers and industry players trying to figure out ways to treat brain tumors. Lawler’s team is developing modifications to peptides to allow them to penetrate the barrier, bind with exquisite specificity to tumor cells and deliver imaging or chemotherapeutic agents to these cells.
In addition to those challenges, tumors are extremely heterogeneous at the cellular level, meaning the cells inside glioblastoma are diverse in their function and genetic characteristics. A drug stopping one of those many functions isn’t sufficient since some cells won’t be affected by the drug and will continue to grow. “This is something I feel the field doesn’t understand properly: how this heterogeneity is generated, what’s the cause, and whether we can tease out, among the differences, some commonality that we can target,” said Lawler.
Lawler also finds promise in collaboration. After hearing a colleague speak about a protein called brevican that’s only detectable and widely expressed in glioblastoma, Lawler was very interested in testing it with his models. “This might be the common target that we’re dreaming of that will allow us to target every glioblastoma cell. That’s what we’re really searching for here. Something we can say ‘here is the target’; it is present on every glioblastoma cell, and it’s not present anywhere else. Let’s develop a drug to target that,” said Lawler. There are over 100 tumors categorized for the brain with many different cell types, and this strategy for treatment could be useful for several different kinds beyond glioblastoma.
Diving into the Shark Tank
Lawler recalls waiting in a room with the Shark Tank speakers in disbelief at how fast the presentations were passing by. Armed only with his visuals and his concept, Lawler walked into the spotlight with a single message in mind. He swayed the audience on his vision for a dream drug that will target a unique molecule expressed by glioblastoma, cross the blood-brain barrier, and deliver drugs to those cells. “It was actually fun to do it, and the time flew. I couldn’t believe it. Five minutes and you’re done—I felt like I had been out there for 25 seconds,” said Lawler.
After his five-minute talk, the audience gave feedback and encouragement that the investigation was heading in an exciting direction. “As scientists, we work hard and we work alone a lot of the time,” said Lawler. “We get rewards, but they don’t come every day. So, it was really encouraging for me to get that kind of acknowledgement.” The grant funding is vital for Lawler and his team to continue collecting data and applying for larger and more sustainable grants to advance research.
Lawler particularly appreciated his time with other investigators away from the crowd—learning about different research and how other PIs leverage funding. He credits BWH with having a strong handle on supporting researchers who want to translate research into reality in a clinical setting. Lawler even came away from the event with contacts at the Translational Accelerator who helped establish a website and presentation to help his lab interact with industry investigators. This helped position Lawler’s lab as a connector between outside investigators and the clinic.