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Threefold approach to improving anticancer drug Biomedical engineers at Duke University have developed a method to address failures in a promising anticancer drug, bringing together tools from genome engineering, protein engineering and biomaterials science to improve the efficacy, accuracy and longevity of certain cancer therapies. Their research has been published in the journal Science Advances.

M

to the therapy. Now, using a combination of three tools — a highly potent protein drug, a ‘depot’ that allows for sustained release of the drug and CRISPR/Cas9based gene editing to pinpoint the cause of resistance

ore than 20 years ago, researchers

to the drug — the Duke team has demonstrated how

discovered that the protein drug TRAIL, short for

they could provide a solution to these problems and

TNF-related apoptosis-inducing ligand, could

give protein-based anticancer ‘biologics’ like TRAIL

effectively kill cancer cells without harming healthy

that failed in the clinic a second chance.

cells — at least, in the lab. TRAIL works by binding

“The real significance of this research for me is the

to specific protein receptors on cancer cells, called

true cross-disciplinary nature of it,” said first author

death receptors, sending a signal that causes the

Mandana Manzari, now a postdoctoral researcher at

cells to self-destruct. Although initial experiments

the Memorial Sloan Kettering Cancer Center. “This is

showed the drug worked in a variety of cancer cell

really the first example I’ve seen where we’re bringing

lines, including melanoma, lymphoma, pancreatic,

in pharmacology, drug delivery and genomics to

prostate, lung, colon and breast cancer, TRAIL and

pinpoint the exact circumstances that cause a biologic

similar drugs surprised researchers by showing limited

to fail and then develop solutions.”

success in clinical trials.

The first step of the process involved addressing

After more study, scientists pinpointed three

TRAIL’s limited potency. Typically, cells have multiple

reasons why the promising drug failed: TRAIL wasn’t

death receptors, but a specific receptor called death

potent enough, the drug was being cleared from the

receptor 5 (DR5) is more prevalent in certain cancer

body too quickly and some cancer cells were resistant

cells. TRAIL, a three-part protein, binds to DR5 and

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