DNA-Demethylating Agents Combined with Histone Deacetylase Inhibitors May Help Combat NSCLC

Combining DNA-demethylating agents (DNA methyltransferase inhibitors) with histone deacetylase inhibitors (HDACis) may pack a double punch against non-small cell lung cancer (NSCLC), according to a recently published study in the journal Cell.  Researchers have found that this novel drug combination therapy appears to prime NSCLC to respond better to  immunotherapy.

The combination therapy triggered a chemical cascade increasing the attraction of immune cells to fight tumors and diminished the work of the cancer gene MYC. Based on these findings, investigators have launched a clinical trial of the combination therapy in patients with advanced NSCLC.

“We were pleased with our findings,” said senior study author Stephen Baylin, MD, who is a professor of oncology and medicine at the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins in Baltimore, Maryland. “It was better news than we had anticipated.”

He said immune checkpoint therapy has been a tremendous step forward. However, he noted that less than half of patients with lung cancer benefit from checkpoint inhibitor therapy. In this current study, he said the two-drug epigenetic therapy combination worked exceedingly well even before adding the immune checkpoint inhibitors.

In a series of experiments, the researchers studied the combination of 5-azacytidine with the three HDACis (entinostat, mocetinostat, and givinostat) in human cancer cell lines and in NSCLC mouse models. The treatments were found to alter the tumor microenvironment. In cancer cell lines, 5-azacytidine worked against the cancer gene MYC, causing down regulation of the entire MYC signaling program; adding the HDACis further depleted MYC. Together, the drugs prevented cancer cell proliferation, simultaneously attracted more immune system T cells to the area of the tumor, and activated these cells for tumor recognition.

In mouse models, the strongest response was observed when using 5-azacytidine plus givinostat. In one mouse model with a mutant form of NSCLC, this drug combination given for 3 months yielded prevention of benign precursor tumors from becoming cancerous and resulted in a 60% reduction of overall area of benign tumor appearance in the lungs. By contrast, a similar group of mice given a placebo universally developed large cancerous lesions in the lungs. Treatment with an alternating schedule of 5-azacytidine with givinostat and 5-azacytidine with mocetinostat not only reduced the growth of rapidly growing primary tumors but also dramatically reduced metastatic occurrence in a second mouse model.

Dr. Baylin and colleagues at Memorial Sloan Kettering Cancer Center in New York and Fox Chase Cancer Center in Philadelphia have started to enroll patients in a phase I/Ib clinical trial to evaluate if giving mocetinostat with guadecitabine can boost immune checkpoint therapy responses in patients with advanced NSCLC. “Thirty to 40 patients are being enrolled. I think it will take a year to start to see if we are getting something special and then we would expand,” Dr. Baylin said in an interview with OncoTherapy Network.