Cancer’s complexity is what originally attracted Aaron Goldman, PhD, to his chosen area of study.
Ever since he started working in a cancer research laboratory his freshman year of college, Goldman, now a bioengineer in the Engineering in Medicine Division at the Brigham, has nurtured his interest in cancer biology and used a combination of math, engineering and biological insights in hopes of finding improved treatments for the fight against cancer.
Battling Cancer Using Nanoparticles
Since the development of cancer is such a complex process, Goldman’s work uses many different perspectives, including bioengineering, cancer biology and mathematical modeling, specifically game theory, to find better ways to fight the disease. Today, the best method for treating cancer is combination therapy, which involves the discrete administration of at least two drugs in the hopes that, cumulatively, these drugs will be able to inhibit the growth of most or all the cancer cells. The problem with administering multiple drugs as separate entities, however, is that tumor cells can rapidly adapt and resist one or more of the drugs in succession, allowing them to survive and continue to multiply.
“Drug resistance is by far the limiting factor in successful treatment of cancer using chemotherapy,” Goldman said. “My group is really interested in looking at the underlying mechanisms of resistance.”
One mechanism is that cancer cells can develop resistance by mimicking other cells in the population that are inherently resistant to the drug. By changing their cell state, they can outsmart serial cancer treatments.
To combat this hurdle, Goldman and his lab developed a method by which two different drugs could simultaneously attack tumor cells and, therefore, reduce the chance of resistance to the treatment. Using a bioengineering approach, they pioneered a 2-in-1 method by which two individual drugs were issued via a single nanoparticle. Their results were recently published in ACS Nano.
A Deeper Look at Cancer’s Microenvironment
While developing this method, Goldman and his team had to take into account the complexity of tumors by finding a solution that would be effective on multiple levels.
“Tumors are heterogeneous,” Goldman said. “They may look very similar macroscopically but on the inside, each cell almost has its own identity whether that’s genetically or phenotypically. This fact is one of the major reasons that chemotherapy fails.”
Using small, engineered nanomedicines, Goldman and his team are able to target drugs to each individual cell on the microscopic level to prevent resistance on the larger scale. They do this, in part, by looking at cells in the context of their microenvironment — that is, the normal cells and extracellular matrix that surround cancer cells and may help them survive.
“We are looking at how all the different characters in a microenvironment contribute to the sustainability of one faction, in this case the cancer cells, which exists in that community,” Goldman said. “If we can start manipulating this faction, the tumor cells around it and all the other cells in the stroma, we can create a drug-sensitive tumor from what would normally be a resistant one.”
For future studies, Goldman is focusing on taking this method a step further by using three-drug combinations and working on maximizing their effectiveness and efficiency. The hardest part about the nanoparticle method, Goldman believes, will be translating this process from in vitro (studying the effects of nanoparticles on cancer cells in a dish) to in vivo (introducing nanoparticles into animal models), the latter of which poses many challenges due to the complexities of organisms’ biological environments, which aren’t relevant in vitro.
“I think that’s a problem that many labs have –- moving from in vitro to in vivo,” Goldman said. “But having good collaborations will overcome that challenge. We are in the process of moving this technology into the clinic so that we can make combinations of drugs that have synergistic benefits and can then tailor them to affect certain types of tumors. We’re focusing our efforts in the clinical translation as immediately and as quickly as we can so that we can make this method a clinical reality.”
As a member of the board of directors for a new biotechnology company, Goldman is already in the process of transitioning the 2-in-1 approach to clinical testing. In addition to his study of nanoparticles, and in a collaboration with Jeff Karp, PhD, a bioengineer at the Brigham, Goldman recently received a Schedule I license to study the therapeutic effects of cannabis. Goldman explains that the next steps for his research will take him in “100 different directions,” but he is embracing new opportunities to collaborate and help improve the lives of patients.
Lessons From Outside the Lab
The transition of the nanoparticle method to clinical stages will require diligence and patience, two qualities Goldman has honed in other areas of his life as well. He has practiced muay thai, Thai kickboxing, for almost 10 years. He was introduced to muay thai during his graduate work in Arizona and even spent a summer training in Phuket, Thailand. Following his first professional fight toward the end of his graduate career, Goldman took a brief hiatus from his practice. When he moved to Boston, he resumed muay thai and spent last winter training in Thailand. He has been able to apply many of the lessons he has learned during his time practicing to his work in the lab.
“When you fight, you don’t just go out swinging your arms,” Goldman explained. “You’ve got to be calculated and think about your next moves. You’ve got to be patient. You learn all of these things in most sports, but for muay thai especially, you can translate some of those lessons into the lab and even when writing and mentoring students.”
One of the biggest lessons that Goldman has learned from his time practicing muay thai is one that he tries to exude in his daily life, including his research.
“A mentor of mine taught me that people have to be rewarded,” Goldman said. “Students have to be encouraged and rewarded and that’s something I always practice in my lab. Communicating that you’ve done a good job really hit home with me and is something that I keep with me in all different aspects of my life.”