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Brain Tumor Research
Barrow scientists go into high gear researching deadliest brain cancer 

 

A group of researchers in a lab at Barrow Brain Tumor Research Center.Glioblastoma multiforme (GBM) is the most common malignant cancer that forms in the brain. It is also the deadliest. Nearly two-thirds of people diagnosed with this aggressive tumor die within a year. Fewer than five percent survive for five years. [source: National Brain Tumor Society] 

“Brain tumors are the deadliest cancers known to man,” says Nader Sanai, MD, a neurosurgeon and researcher at Barrow. “They are extremely ruthless, and they have been, to date, resistant to any of our treatment efforts.”

The obstacles to treating brain tumors are both internal, due to the nature of the brain and the tumors that affect it, and external, due to limited resources and the nature of clinical research.

Solving these challenges requires a multifaceted approach that involves understanding how tumors form and migrate, developing ways to deliver treatments and testing those treatments. Scientists in the Barrow Brain Tumor Research Center (BBTRC) are uniquely positioned to accomplish these goals.

“When I arrived, Barrow had one of the largest, if not the largest, operative brain tumor volumes in the United States, but didn’t really have a research program that was commensurate with that,” explains Dr. Sanai, who is director of the BBTRC and also leads one of its three labs. “We tried to create a complementary system where we would develop basic science, translational science and clinical research that would take advantage of the clinical volume.”

Although surgeons can often remove the main mass of a brain tumor, some cancerous cells remain behind. Radiation and chemotherapy have proven ineffective at stopping the recurrence of cancer.

Developing highly targeted drug therapy

Shwetal Mehta, PhD, is a molecular biologist who came to Barrow from the Dana Farber Cancer Institute and leads one of the BBTRC labs. She studies the biology of tumor cells in order to find better ways to stop them.

Dr. Mehta’s research focuses on a protein called olig2, which is expressed in stem cells in the brain. It is also involved in malignant brain tumors, because it blocks the function of a tumor suppressor gene. This allows tumor cells to proliferate out of control.

Olig2 is a good target for drug therapies because it is only expressed in the central nervous system. Treatments that knock it out would not harm the rest of the body. However, it exists in healthy brain cells as well as tumors, so blocking it completely could damage those cells. Dr. Mehta is trying to identify interactions between olig2 and other proteins that are involved in cancerous growth. Drugs that block those interactions could stop tumor growth without harming healthy tissue.

“The whole idea is coming up with highly targeted therapies so you’re not treating patients with drugs that can affect all of your cells,” she says.

Halting tumor growth is just one part of the solution, however. Research suggests that shutting off tumor growth might signal cancerous cells to migrate to other parts of the brain, invading healthy tissue.

Testing drugs in 3D

To learn more about what triggers cells to migrate, Dr. Mehta is working with Rachael Sirianni, PhD, a biomedical engineer who leads another lab in the BBTRC. Dr. Sirianni has developed special scaffolds for growing cell cultures in 3D instead of in a flat petri dish. When cells are moved into a two-dimensional medium, their behavior changes. They may become more sensitive to drugs, for instance. And brain tumor cells typically lose their invasiveness. As a result, testing drugs in 2D cultures is likely to give misleading results.

“Cells behave fundamentally different in 3D,” explains Dr. Sirianni. “When we make a scaffold, the cell can move in three dimensions; it can attach to things and pull and grab. We try to design these scaffolds to capture essential elements of the brain.”  

Foiling the blood-brain barrier

A researcher in the lab at Barrow Brain Tumor Research Center.One of the main obstacles physicians face in treating brain tumors is getting drugs past the blood-brain barrier. This barrier prevents potentially harmful materials in the bloodstream from getting into the brain. Unfortunately, it tends to block out the drugs, as well.

Dr. Sirianni designs nanoscale polymers—molecules arranged in a repeating structure—as carriers to transport drugs into the brain. After the particles slowly release their drugs, they will break down and be safely eliminated by the body.

“My lab focuses on designing the particles to interact specifically with the target tissue. We design them to get taken up into the brain and to be delivered specifically to brain tumors,” she says.

All cells in the body are surrounded by membranes. These membranes contain receptors that allow certain materials into the cell while keeping others out.

“What we do is attach things to the surface of our particles that interact specifically with the cell surface receptors on the blood-brain barrier and on the tumor,” she says.

One way she studies how to get particles into the brain is by looking at diseases that have already mastered this technique.

“Rabies is a good example. Rabies virus is extremely effective at reaching the brain,” she says. “So we take a part of the virus that doesn’t cause an immune reaction or any toxic effects. We take the part of the virus that enables it to travel along the nerve and put that on our particle, and we find our particles are able to get into the brain.”

Speeding up discovery via phase 0 trials

Dr. Mehta’s work on understanding what causes cells to go “rogue” can provide important direction for drug development. And Dr. Sirianni’s work in drug delivery can help the resulting therapies hit the right targets. But new treatments require extensive, expensive testing before they can be brought to market.

“What we’ve run into year after year are a series of failures in our clinical trials and millions, even billions of dollars going toward development of drugs that ultimately don’t pan out,” says Dr. Sanai.

To save time and money while identifying promising treatment candidates, he is planning a series of phase 0 clinical trials.

Traditionally, drug trials occur in three phases. Phase 1 evaluates a drug’s safety in humans. Phase 2 determines if it is effective. Phase 3 involves a larger group of subjects to confirm effectiveness and monitor side effects.

The FDA created phase 0 trials as a way to bring new drugs to market faster. These trials involve very small numbers of subjects who receive sub-therapeutic doses of the drug being tested. Dr. Sanai will give patients a small dose of experimental drug before surgically removing their tumors. He can then test the patient as well as the tumor to see if the drug arrived at the tumor and whether it is modulating the target as intended.

“If those two things are happening, then you know that the drug could be a winner, and it’s something that’s worth investing more time and money in pursuing through larger and more extensive trials,” he says. “On the flip side, if it’s not achieving those fundamental goals, then you know very quickly that you don’t need to pursue this drug any further.”

While phase 0 trials would cost several hundred thousand dollars to conduct, phase 1 or 2 trials typically require about $10 million. For brain tumor research in particular, this cost difference is critical.

“Brain tumor research doesn’t get the resource allocation that other cancers get because it is less common, number one,” explains Dr. Sanai. “Number two, there’s less survivorship, so there’s less of a voice in support of this kind of research. And number three, because the clinical market is small, pharmaceutical and biotech companies are less likely to choose this tumor as a target for therapy.”

He has several trials lined up already with Merck, Novartis and other pharmaceutical companies.

“We’ve been very impressed with the response we’ve gotten from industry in terms of their enthusiasm for this,” he notes. “What we’re essentially doing is tilting the tables to remove any barriers they might see in terms of allowing their drugs to be investigated in brain tumor patients.”

Partnering with others

Scientists in the BBTRC also collaborate with local companies and universities to broaden their capabilities.

“It’s about leveraging our local assets, whether it’s with Arizona State University, whether it’s with TGen, whether it’s our affiliation with the cancer center at the University of Arizona. We think all boats will float if we work together,” Dr. Sanai says.

All of the researchers cite Barrow’s rare combination of research and clinical work as a tremendous strength. “Many of the problems I deal with in the operating room are ultimately going to be solved in the lab,” Dr. Sanai says.

“I feel that the only way to make progress in the field is to push on both fronts. That’s what I’m here for.”

 

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