SWCRF-supported research at Johns Hopkins discovers drug combination that may boost immunotherapy responses in lung cancer patients.

 

Stephen B. Baylin, MD

The Samuel Waxman Cancer Research Foundation (SWCRF) congratulates longtime grantee Stephen B. Baylin, MD, whose research team at Johns Hopkins Kimmel Cancer Center have identified a drug combination therapy that could prime nonsmall cell lung cancers to respond better to immunotherapy. These epigenetic drugs, used together, achieved robust anti-tumor responses in human cancer cell lines and mice.

Johns Hopkins has opened a Phase 1 trial to study the effects of the combination treatment in patients with advanced, nonsmall cell lung cancer in collaboration with Memorial Sloan Kettering Cancer Center and Fox Chase Cancer Center. The SWCRF is one of several funding organizations that have supported this work.

A paper published in November in the journal Cell, detailed the work of a team of researchers -- led by graduate student Michael Topper; research associate Michelle Vaz, Ph.D.; and Dr. Baylin -- that combined a demethylating drug called 5-azacytidine that reactivates some cancer suppressor genes, with one of three histone deacetylase inhibitor drugs. The inhibitors work against proteins that can contribute to cancer development. The combination therapy triggered a chemical cascade that caused immune cells to fight tumors and diminished the impact of a cancer-causing gene called MYC.

“In our study, the two-drug epigenetic therapy combination worked exceedingly well, even before putting in the immune checkpoint inhibitors,” Dr. Baylin said. “In animal models of lung cancer, the two agents either prevented cancer from emerging or blunted the effects of more aggressive cancers. In both scenarios, a large component of the results involved an increase in immune recognition of the tumors.”           

In a series of experiments, researchers studied the combination of 5-azacytidine with three inhibitor drugs in human cancer cell lines and in mouse models of nonsmall cell lung cancers. In cancer cell lines, 5-azacytidine caused down regulation of the entire MYC signaling program. Adding the inhibitors further depleted MYC, and together the drugs caused actions that prevented cancer cell proliferation, simultaneously attracted more immune system T cells to the area of the tumor and activated these cells for tumor recognition.

“This work demonstrates that epigenetic therapy can change the behavior of cancer cells by reprogramming gene information, which is the mission of the SWCRF Institute Without Walls and long-term member Steve Baylin,” said Dr. Samuel Waxman, Founder and CEO of the SWCRF. "We thank our donors for making this scientific progress possible through their support and look forward to future developments in this excellent work.”

In one mouse model with a mutant form of nonsmall cell lung cancer, the combination of  5-azacytidine and the inhibitor givinostat prevented benign, precursor tumors from becoming cancers and caused 60 percent reduction of overall area of benign tumor appearance in the lungs. By contrast, a group of mice with the same form of lung cancer that were given a mock treatment developed large, cancerous lesions in the lungs.

In a second model of mice with established, aggressive, nonsmall cell lung cancer, treatment with an alternating schedule of 5-azacytidine with givinostat and of 5-azacytidine with mocetinostat not only reduced the growth of established, rapidly growing primary tumors but also dramatically reduced metastatic occurrence.

In addition to Topper, Vaz and Baylin, other scientists contributing to the Cell paper include Michael J. Christina DeStefano Shields, Noushin Niknafs, Ray-Whay Chiu Yen, Alyssa Wenzel, Jessica Hicks, Matthew Ballew, Meredith Stone, Phuoc T. Tran, SWCRF grantee Cynthia A. Zahnow, Valsamo Anagnostou and Victor E. Velculescu of Johns Hopkins; Katherine B. Chiappinelli of the George Washington University Cancer Center; Matthew D. Hellmann of Memorial Sloan Kettering Cancer Center; and Pamela L. Strissel and Reiner Strick of the University-Clinic Erlangen in Germany.

 

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