Combination therapy attracts immune cells to fight tumors and blocks the cancer gene MYC Johns Hopkins Kimmel Cancer Center researchers and colleagues have identified a novel combination drug that works best without ‘ y lung cancer cells to better respond to immunotherapy. So-called epigenetic therapy drugs, used together, achieve strong anti-tumor responses in human cell lines and cancer.
Credits: Michael Topper and Michelle Vaz
Researchers and colleagues at the Johns Hopkins Kimmel Cancer Center have identified a novel combination drug that could be the most important non -cellular lung cancers that are more resistant to resistance. So-called epigenetic therapy drugs, used together, achieve strong anti-tumor responses in human cell lines and cancer.
During the study, it was published November 30, 2017, in the journal Cell, a group of researchers led by graduate student Michael Topper; research fellow Michelle Vaz, Ph.D .; and senior author Stephen B. Baylin, MD, combined a demethylating drug called 5-azacytidine with chemical dominance of certain cancer suppressor genes with one of the three histone deacetylase inhibitor drugs (HDACis). HDACis works against proteins called histone deacetylases that are involved in processes, such as cell replication and division, and may contribute to the development of cancer. Combination therapy activates a chemical cascade that increases the attraction of immune cells to fight tumors and reduces the work of MYC cancer. Consistent with the findings, the investigators launched a clinical trial of combination therapy in patients with advanced, nonsmall cell lung cancer.
The development of treatment modalities for patients with lung cancer is a critical medical need, according to Baylin, Virginia and Daniel K. Ludwig Professor of Cancer at Kimmel Cancer Center. While immune checkpoint therapy is “a huge step forward, less than half of patients with lung cancer have benefited to date,” he said.
“In our study, the two drug epigenetic therapy combination worked very well, even before putting resistances at the immune checkpoint,” Baylin said. “In animal models of lung cancer, both agents prevent the onset of cancer or suppress the effects of more aggressive cancers. In both scenarios, a large proportion of the consequences are involved. to increase immune recognition of tumors.
In a series of experiments, the researchers studied the combination of 5-azacytidine with HDACis entinostat, mocetinostat or givinostat in human cancer cell lines and in mouse models without lung cancer. cell. Treatments have been found to alter the tumor microen environment In cancer cell lines, 5-azacytidine works against the cancer gene MYC, causing a reduction in regulation of the entire MYC signaling program. The addition of HDACis further depletes MYC, and simultaneously the drugs cause actions that inhibit cell proliferation, simultaneously attracting multiple immune system T cells to the tumor site and activating these cells for to identify the tumor.
In mouse models, the strongest response was found when 5-azacytidine plus givinostat was used. In a mouse model with a mutant form of nonsmall cell lung cancer, this combination of drugs given for three months provided prevention of benign, precursor tumors from becoming cancers and caused a 60 percent reduction. in the general area of the benign tumor seen in the lung. In contrast, a group of mice with the same form of lung cancer given a proud treatment around the world produced large, lung cancer lesions.
In a second model of mice with stable, aggressive, non-stable lung cancer, treatment with an alternating schedule of 5-azacytidine with givinostat and 5-azacytidine with mocetinostat was not limited to reduced the growth of established, rapidly growing primary tumors but also significantly reduced metastatic occurrence.
Baylin and colleagues at Memorial Sloan Kettering Cancer Center in New York and Fox Chase Cancer Center in Philadelphia began a phase I / Ib clinical trial to examine whether giving mocetinostat a 5-azacytidinlike drug. called guadecitabine can increase immune checkpoint therapy responses in patients with advanced, non -cell lung cancer The trial is part of the Van Andel Research Institute – Stand Up To Cancer Epigenetics Dream Team and funded by Merck through Stand Up To Cancer (SU2C) program by Catalyst, an initiative led by SU2C that will bring rapid cancer treatment to patients. Matthew Hellmann, MD, an author of the paper, will lead this test on Memory Sloan Kettering, and Jarushka Naidoo, MBBCh., assistant professor of oncology, heads Johns Hopkins. For more information, click HERE.
In addition to Topper, Vaz and Baylin, other scientists have contributed to Cell along with the role are Michael J. Christina DeStefano Shields, Noushin Niknafs, Ray-Whay Chiu Yen, Alyssa Wenzel, Jessica Hicks, Matthew Ballew, Meredith Stone, Phuoc T. Tran, Cynthia A. Zahnow, Valsamo Anagnostou and Victor E. Velculescu’s Johns Hopkins; Katherine B. Chiappinelli of George Washington University Cancer Center; Matthew D. Hellmann of Memorial Sloan Kettering Cancer Center; and Pamela L. Strissel and Reiner Strick of University-Clinic Erlangen in Germany.
The work was supported by grants from the Hodson Trust, Drs. Miriam and Sheldon G. Adelson Medical Research Foundation, Stand Up To Cancer’s Jim Toth Sr. Breakthrough Lung Cancer Research Award, the Commonwealth Foundation for Cancer Research and the Samuel Waxman Cancer Research Partnership Foundation for a Cure. It is also supported by National Institutes of Health grants (CA12113, CA006973, CA180950) and the Van Andel Research Institute-Stand Up To Cancer Epigenetics Dream Team.