Attacking Tumors

UM's Rich Bridges and protein that's key to blocking brain tumors

UM center partners with pharmacy
company to create new therapies

Movies about scientific discoveries — “A Beautiful Mind,” “The Theory of Everything” — usually involve dramatic revelations: A single mathematical equation unlocks
the answer to a larger question about the universe, or a lone scientist’s microscope reveals a cure for disease.

In real life, of course, scientific discoveries don’t fit so neatly into one edited stroke of genius. But when they do emerge, their implications for the world of science and medicine are as intriguing as any big-picture biopic.

“You don’t have many light-bulb moments,” says Richard Bridges, Regents Professor of Pharmacology and Toxicology in the University of Montana Department of Biomedical and Pharmaceutical Sciences. “You have many moments spread out over time that lead to breakthroughs. It’s like an actor becoming an overnight success, but really they’ve been working at it for years.”

For Bridges and a research team at UM’s Center for Structural and Functional Neuroscience, it took almost two decades of experimentation to arrive at two related breakthroughs. They offer a potential treatment for brain tumors, which is an area in dire need of new therapies. It’s also great news because the now-patented research has led to an exclusive agreement with a drug company – and that kind of commercial development has resounding economic effects for the University and the Missoula community.

The discoveries in the group began with transporters – tiny proteins found on the surface of cells, which Bridges describes as turnstiles or revolving doors that move small molecules into and out of cells. Experimenting with those revolving doors has been a major focus for a number of groups in UM’s neuroscience center since its inception in 2002.

In order to truly investigate the characteristics of the transporters, medicinal chemists, biochemists and neuroscientists in the department worked together using a collaborative approach that reflects the philosophy on which the center was founded.

There are all kind of transporters in the body, and the UM team had a family of transporters in the brain they were interested in studying. Naturally, they started looking for cells featuring that particular type, and in that quest they discovered something unexpected: The cells that expressed their particular transporters in the highest amounts were brain tumor cells.

“About the same time other scientists who were studying brain tumor cells also happened upon the presence of these transporters,” Bridges says. “They looked at it from the cancer side, and we looked at it from the biochemistry side.”

That discovery, which happened around 2004, changed the course of the team’s work. They started looking specifically for compounds that would inhibit the transporter.

“You have a protein on the outside of the cell whose job it is to move molecules from the outside to the inside, and it’s found on tumor cells,” Bridges says. “So a good guess would be that it is really important to helping that tumor cell survive. We thought inhibiting that transporter might compromise the ability of tumor cells to grow – and it turns out that’s the case.”

Nicholas Natale, a chemist working at the University of Idaho at the time, went to a seminar by UM chemist Charles Thompson and heard about the center’s experiments. He was working on designing molecules isolated from the Amanita muscaria, which resemble the Super Mario mushroom, that served as inhibitors. At their request, he sent a box of the compounds to the center at UM to see if they’d work, and they did.

“We got a hit for that particular transporter,” Natale says. “And in 2007 I was invited to move to Missoula to work at UM.” He joined the core team of professors, which along with Bridges and Thompson includes Sarjubhai Patel and Philippe Diaz.

The other major breakthrough for the group happened fewer than two years ago. While modifying the inhibitors to make them more potent, the group discovered these compounds were working at a new site on the transporter that was different from where the other inhibitors acted. It wasn’t a “transporter site” but a “regulatory site” that no one else knew about.

“The transporter is like a lock on a door,” Bridges says, “with the inhibitors acting like keys that block the lock and prevent it from working. Finding the regulatory site was like discovering the dead bolt and having an entirely new set of keys. Now we are focused on developing new drugs that only hit that regulatory site. Those drugs will probably be much more specific at inhibiting just our desired transporter, as well as more potent.”

For the past few years, the team at UM’s neuroscience center also has consulted for Promentis Pharmaceuticals Inc., a company developing drugs that work on the same family of transporters, but for other neurological disorders and not cancer. When Promentis caught wind of the group’s investigations on brain tumor cells and new lead compounds, they were intrigued. With an already solid background of collaboration under their belts, the center and the company formed a partnership that includes licensing and research agreements.

Research at UM’s biomedical and pharmaceutical sciences department also matters on an economic development level. Over the years, the Montana Board of Research and Commercialization Technology – an organization within the Montana Department of Commerce that works to facilitate commercialization of research discoveries – has awarded the center grant money. This helps turn their basic neuroscience discoveries funded by federal grants into potential products to diagnose or treat neurological diseases.

Total federal funding in just the neuroscience center amounted to about $13 million in the past five years. About 60 to 70 percent of that money goes to salaries, which help support more than 40 people. So even without a commercial component, the department’s basic research creates jobs. And because students, especially undergraduate students, are so involved with this basic research, the economic impact on them also is great. They can earn good wages in the labs and valuable experience for future careers.

“That’s really important to appreciate,” Bridges says. “When faculty researchers at UM get a multimillion-dollar research grant, that shouldn’t be viewed economically as any different than if a Montana company receives a multimillion-dollar defense contract.

Unfortunately, people don’t think of those as the same. But these are real jobs, and they’re high-tech jobs. And because they are funded by grants it is actually money from outside the state coming in. So it’s new dollars with an even greater economic impact.”

The Promentis agreement adds one more layer of potential economic development. If all goes well, the partnership with UM could create more jobs and continue putting money back into the local economy. It will take some time. As with all real-life discoveries, the road to clinical testing involves myriad tests.

“We still don’t know if our inhibitor can be developed into drugs,” Bridges says. “We haven’t looked at delivery into the brain; we haven’t looked at toxicity.

But that’s the type of work these days that you have to do in collaboration with a pharmaceutical company because they have the funding and expertise to do it.”

It’s the deliberate collaboration between UM’s chemists, neuroscientists, biochemists and pharmacologists that makes it possible for the University to carry the project to this point. Never mind that UM doesn’t have a medical school: The fact that the neuroscience center’s team discovered a way into cancer research is part of the magic of a university that does basic research.

“If I was to tell you the work I was doing before it was related to cancer, you might say ‘How relevant is that?’” Bridges says. “We didn’t know where it was going to go. But if you do good basic science, it almost always lays the foundation for important work. Six years ago I would not have called my lab a cancer lab, and now we’re not really a cancer lab – we’re doing the same chemistry we’ve always done – but now we have a target that’s related to cancer.”

— By Erika Fredrickson

UM faculty member Sarjubhai “Sarj” Patel (third from left) works with undergraduate researchers (left to right) Maxx Nehser, Daithi Martin and Dillon Schweitzer.

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