An interview with Dr. Sunit Das on using repurposed drugs to fight the deadliest brain cancers.
Imagine a fortress designed to protect your most vital organ. Its walls are incredibly selective, allowing in only the most essential supplies while keeping out toxins, pathogens, and—crucially—life-saving medicines. This is the Blood-Brain Barrier (BBB), a magnificent and frustrating biological shield. For patients with glioblastoma, one of the most aggressive and lethal brain cancers, the BBB is a primary reason why treatments so often fail. But what if we could temporarily open a gate in this fortress, just long enough for our best drugs to get through? We sat down with Dr. Sunit Das, a leading neuro-oncologist and surgeon, whose team is pioneering a revolutionary approach: using a common heart medication as a key to unlock the brain.
To appreciate Dr. Das's work, we must first understand the barrier itself. The BBB isn't just a wall; it's a sophisticated, cellular security system lining the blood vessels of the brain.
"Think of it as a tightly-knit layer of endothelial cells, sealed together with what are called 'tight junctions'," Dr. Das explains. "These cells are supported by other specialized cells, like astrocytes, which act like mission control, telling the barrier what to let in and what to keep out."
This system is essential for health, but it's a nightmare for treating brain tumors. "Over 98% of small-molecule drugs and nearly 100% of large-molecule drugs cannot cross this barrier," says Dr. Das. "We have powerful chemotherapy agents that can shrink tumors in a petri dish, but they never reach their target in a patient's brain."
of small-molecule drugs cannot cross the BBB
of large-molecule drugs cannot cross the BBB
For decades, scientists have tried to force the BBB open with brute force, often causing more harm than good. Dr. Das's team took a different path.
"We became fascinated with a cellular transport system called RMT, or Receptor-Mediated Transcytosis," he says. "It's one of the brain's own supply routes. The BBB has specific 'gates' for essential molecules like insulin and iron. We wondered if we could hijack one of these gates."
Their search led them to an unlikely candidate: Imatinib, a drug widely used to treat leukemia. "Imatinib, we discovered, doesn't just inhibit cancer cells; it also temporarily and reversibly interferes with a specific protein (PDGFR-β) that helps maintain the tight junctions in the BBB. In essence, it gently loosens the bricks in the wall without tearing it down."
Imatinib, a leukemia drug, was found to temporarily and reversibly loosen the tight junctions of the Blood-Brain Barrier, creating a window for chemotherapy drugs to reach brain tumors.
To test their hypothesis, Dr. Das's team designed a critical experiment.
They used a mouse model of glioblastoma, implanting human glioblastoma cells into the brains of laboratory mice.
The mice were divided into three groups:
A fluorescent tag was attached to the TMZ, allowing the researchers to visually track its journey and concentration using advanced imaging.
Tumor size and mouse survival were meticulously tracked over 60 days.
The results were striking. The imaging data showed a dramatic increase in the concentration of TMZ within the brain tumors of the Combo Therapy group.
| Group | Treatment | TMZ Concentration in Tumor (µg/g) |
|---|---|---|
| A | Control (Saline) | 0.0 |
| B | TMZ Alone | 1.8 |
| C | Imatinib + TMZ | 9.4 |
Pre-treatment with Imatinib led to a more than 5-fold increase in the delivery of the chemotherapy drug Temozolomide to the brain tumor.
This enhanced drug delivery had a direct and powerful impact on survival.
| Group | Treatment | Median Survival (Days) | Survival at 60 Days |
|---|---|---|---|
| A | Control (Saline) | 28 | 0% |
| B | TMZ Alone | 36 | 10% |
| C | Imatinib + TMZ | 54 | 60% |
The combination of Imatinib and TMZ significantly extended both median and long-term survival compared to the standard treatment.
Crucially, the treatment was safe. Analysis of healthy brain tissue showed that the BBB disruption was temporary and localized primarily to the tumor region, minimizing the risk of brain swelling or toxicity.
| Group | Treatment | TMZ in Healthy Brain (µg/g) |
|---|---|---|
| B | TMZ Alone | 0.5 |
| C | Imatinib + TMZ | 1.1 |
While Imatinib increased TMZ penetration in healthy tissue slightly, the concentration remained low, indicating a favorable safety profile focused on the tumor area.
Visual representation of the 5-fold increase in drug delivery with Imatinib pre-treatment
Dr. Das emphasized that this breakthrough rests on a foundation of specific, high-quality research materials. Here are some of the key tools used in his lab.
The "seeds" of the tumor, used to create an accurate and reproducible disease model in mice.
The "trackable missile." The fluorescent tag allows researchers to visually confirm and quantify drug delivery to the tumor.
A specific tool used to detect and image the target protein on the BBB, confirming the mechanism of action.
These kits make the invisible visible, allowing scientists to stain and visualize the tight junction proteins (like ZO-1) to see how they change after Imatinib treatment.
The "camera" that captures detailed, 3D images of the brain tissue, showing exactly where the fluorescent drug has accumulated.
"This isn't a cure," he is quick to clarify, "but it's a potentially transformative strategy. We're not developing a new drug from scratch, which is incredibly time-consuming and expensive. We're finding a smarter way to use the tools we already have."
The implications are vast. If successful in human trials, this approach could be a platform technology, potentially used to deliver a wide range of drugs for other neurological diseases like Alzheimer's or brain infections.
"For too long, the blood-brain barrier has been our greatest adversary," Dr. Das concludes, a determined glint in his eye. "We're learning to see it not as a wall to be smashed, but as a door to be unlocked. And we may have just found one of the keys."
Dr. Sunit Das is a Senior Scientist at the Institute for Neurological Discovery and a practicing neurosurgeon. His work is supported by the National Institutes of Health and the Global Brain Cancer Research Initiative.