Peeling away pancreatic cancers’ defenses

At Winship Cancer Institute, pancreatic cancer researcher Greg Lesinski and colleagues have a new paper in Molecular Cancer Therapeutics. It’s about a combination immunotherapy approach that gets through pancreatic cancers’ extra defenses, and it represents the preclinical counterpart to a clinical trial that is underway and almost finished at Winship, under the direction of GI oncologist Bassel El-Rayes.

Immunotherapies have transformed how other forms of cancer are treated, but for pancreatic cancers, an obstacle is getting through the dense layers of cellular shielding that the cancers build around themselves. Pancreatic cancers create “nests” of fibrotic stellate cells that pump out inflammatory cytokines such as IL-6.

Pancreatic cancer is anticipated to become the second deadliest cancer in the United States by 2030, surpassing breast and colon cancer. 

“Inflammation and a good immune response don’t always go hand in hand,” El-Rayes told us, for a 2018 Winship magazine article. “High IL-6 causes immune exhaustion, and keeps the good cells out of the tumor.”

Lesinski and El-Rayes wanted to know if an inhibitor of Hsp90 called XL888 could enhance sensitivity to immunotherapy agents, also known as checkpoint inhibitors. Hsp90 is a heat shock protein that acts as “chaperone” (protein folding assistant) to several inflammatory regulators, including those connected with IL-6.

In the new paper, Lesinski’s lab showed that XL888 could inhibit the growth of pancreatic stellate cells and decrease IL-6 production. It also enhanced the activity of checkpoint inhibitors against pancreatic cancers in mice, increasing the ability of immune cells to infiltrate the tumors. The first author of the paper was visiting medical student Yuchen Zhang.

We look forward to the clinical trial results and more about additional complementary approaches against IL-6 from Lesinski’s lab.

Posted on by Quinn Eastman in Cancer Leave a comment

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Quinn Eastman

Science Writer, Research Communications 404-727-7829 Office

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