Nano-caging gives a failed cancer drug new life
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BIND Therapeutics describes itself as bringing nanotechnology to cancer therapy, but with an achievement announced on Wednesday a more colloquial description might be apt: The Cambridge-based biotech could help bring failed cancer drugs back from the dead — and all because of clever molecular packaging.

In a study reported in Science Translational Medicine, scientists from BIND joined forces with a team from AstraZeneca to take a cancer drug the British pharmaceutical company had essentially abandoned, encase it in a molecular cage called a nanoparticle, and give it to lab rodents implanted with human cancers. Compared to the uncaged drug, the nano-enclosed version was more effective and less toxic.

“The interesting part of this study is that the [nano-cages] dramatically changed the pharmacology” of the cancer drug, said David Bearss, chief executive of Tolero Pharmaceuticals, a cancer therapeutics company in Lehi, Utah. The nanoparticles “effectively increased the concentration of the [drug] where it needs to be,” and kept it away from bone marrow, where it is toxic. Bearss wrote an accompanying commentary published Wednesday but was not involved in the study.

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Countless cancer drugs have succeeded in lab rodents only to fail in people, so it’s premature to expect the nano-caged drug to work in patients as effectively and safely as it did in rats and mice. Only large human studies will show that. But the results, submitted to the journal last August, were encouraging enough that in October AstraZeneca launched a clinical trial of the caged drug, recruiting patients with advanced solid tumors at sites in Colorado, Florida, and Tennessee.

There were high hopes for the original, uncaged version of the AstraZeneca drug, called barasertib, when the company unveiled it more than a decade ago. A molecularly targeted drug like Gleevec or Iressa, barasertib didn’t just kill dividing cells willy nilly, as chemotherapy drugs do. It disrupted a specific enzyme — one whose overactivity seemed to fuel breast and pancreatic tumors, among other cancers. By inhibiting the enzyme, barasertib would halt the proliferation of cancer cells, AstraZeneca hoped.

But the drug stalled out in early clinical testing. Although barasertib showed some promise in treating leukemia, it demonstrated little benefit against solid tumors, and it proved toxic to bone marrow in cancer patients of all stripes, killing off their white blood cells. AstraZeneca suspended barasertib’s development in 2011.

Craig F. Walker/The Boston GlobeStephen Zale, head of discovery and research at BIND Therapeutics, at the company’s headquarters in Cambridge, Mass.

BIND, cofounded 10 years ago by MIT bioengineer Robert Langer and Brigham and Women’s Hospital physician-nanotechnologist Dr. Omid Farokhzad, focuses on what it calls Accurins — nanoparticles consisting of polymers that have a long track record in medicine, plus polyethylene glycol, a compound often used as a laxative.

The company is developing these nanomedicines by the bucketful, designing each kind of Accurin to target specific cells, always with the same goal: to deliver a drug (the company is starting with cancer drugs) only to tissues where it is needed and in ways that release the drug safely and effectively.

In the new study, BIND scientists used every trick in the nano-chemists’ handbook to build Accurins for barasertib. They had to find structures that released the drug only to tumors, sparing healthy tissue, and at a rate slow enough to be much less toxic than the uncaged drug. The scientists, led by the company’s vice president for research and discovery Stephen Zale, then tested various drug-enclosing cages on human colorectal cancers that had been implanted into lab rats and mice, and on human lymphomas transplanted into mice.

Two of the cages worked especially well compared to uncaged drug in the rodent models. In the mice with human colorectal tumors, for instance, half the dose of the caged drug cut tumor growth by 96 percent, while a full dose of the uncaged drug cut tumor growth by only 65 percent.

In all cases, the caged drug basically spared the animals’ bone marrow, while the uncaged drug was toxic. The reason, said Zale, is that naked drug molecules are so tiny they seep out of blood vessels and reach all sorts of unintended tissues, like marrow. But the molecular cage is large enough to keep the drug inside blood vessels — except for those around tumors, which are leaky.

Result: the drug “passes through the leaky blood vessels into the tumor,” Zale said.

The findings raise the possibility “that this approach could be used to rescue many failed drug programs,” said Bearss.

Such rescues, noted Langer, are “just the tip of the iceberg of what Accurins and nanotechnology can achieve.”

For instance, one experimental drug that BIND is currently testing in Phase 2 trials for patients with lung, prostate, and other cancers encases the chemotherapy drug docetaxel in a nanoparticle that makes a beeline for molecules found on the surface of tumors, but spares healthy tissue.

The target-finding ability of Accurins can “open the door for using nanoparticles for all kinds of new therapeutics that were difficult if not impossible,” Langer said.

In addition to its work with AstraZeneca, BIND has collaborations with such drug giants as Pfizer, Roche, and Merck to develop Accurin cages.

It has been a long slog, with investors concerned that the cancer nano-drugs that BIND is developing on its own have had “good but not great” results, while the drugs it is developing with partners “belong to unproven drug classes,” as a Credit Suisse analyst said in 2014.

BIND went public in 2013 at $15 per share and was trading on Wednesday at about $1.35.

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