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Gel, Crispr Help Defeat Cancer Drug Obstacles

Crispr-Cas9 illustration

Crispr-Cas9 illustration (LBL.gov)

17 Sept. 2019. A high-powered binding protein, formulated as a gel and targeted by Crispr gene editing is shown in lab mice to precisely deliver drugs and kill cancer cells. A description of the technology and test results by a team from Duke University in Durham, North Carolina appear in the 4 September issue of the journal Science Advances.

Researchers from the biomedical engineering lab of Ashutosh Chilkoti and pharmacology lab of Kris Wood at Duke seek to overcome continuing obstacles in developing effective treatments for cancer. A promising class of small-molecule drugs known as tumor necrosis factor–related apoptosis-inducing ligand, or Trail, is shown in lab tests over the years to kill a range of solid tumor cells in breast, lung, colon, melanoma, lymphoma, pancreatic, and prostate cancer. In real-world tests, however, Trail drugs repeatedly fail due to lack of binding ability to targeted tumor cells, short effective potency times, and resistance built-up to Trail drugs by the tumors.

The team led by graduate student Mandana Manzari, now a postdoctoral researcher at Memorial Sloan Kettering Cancer Center in New York, designed a strategy to address these limitations. Trail drugs promote cell apoptosis or death by sending chemical signals to receptor proteins that kill the cells from inside. Manzari and colleagues designed a six-part death-receptor agonist that binds to a site called DR5, sensitizes target cells to the drug, and sends more intense chemical signals, making it extremely toxic. Tests with human cancer cell lines in lab cultures confirmed this cancer-cell killing power.

The researchers then created a delivery method for longer-term release of this death-receptor agonist. For extending the release time of the drug, the team designed a gel material made from elastin-like polypeptides, short chains of biocompatible polymers used previously for drug delivery and tissue engineering. Elastin-like polypeptides are temperature-sensitive and can fuse with the delivered drug. In this case, the elastin-like polypeptides are formulated as a liquid for easier injection at room temperature, but when subjected to body temperature, they form into a gel that adheres for longer periods to the tumor.

To help overcome resistance to Trail drugs developed by tumors, the researchers assessed the genetics of tumor cells with the gene-editing technology Crispr, short for clustered, regularly interspaced short palindromic repeats. Using the editing enzyme Cas9, the team systematically knocked-out genes in the target tumor cells until they found the genes contributing to resistance to death-receptor agonists, or DRAs.

“When we figured out the genes that drive resistance,” says Manzari in a Duke University statement, “we were able to map them to commercially-available drugs that could specifically target the proteins that come from those genes. It basically gave us a platform to figure out what drugs we can combine with the DRA in cases where this drug or other protein drugs don’t work well to nip that resistance in the bud.”

The researchers tested their death-receptor agonist, formulated into a liquid that transforms into a gel, targeted to overcome tumor resistance. The test subjects were lab mice grafted with human colon cancer tumor tissue, receiving combinations of two or three small-molecule Trail drugs and death-receptor agonist, against the death-receptor agonist alone. The results show mice receiving the gel-delivered death-receptor agonist and three cancer drugs have less tumor growth and longer survival times than the two-drug combinations or death-receptor agonist alone.

The team believes they designed a cancer therapy strategy that fits into the emerging precision-medicine treatment model. Duke University has patents granted or applications filed for the technologies developed in this research, with the lead and senior authors listed as inventors. In addition, Chilkoti is the scientific founder and adviser to PhaseBio Pharmaceuticals Inc. in Malvern, Pennsylvania that licenses his work on fusion of elastin-like polypeptides to drug compounds.

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