Epigenetic therapy holds promise for cancer management

Jan 12 2011

Syndax, a clinical-stage epigenetics oncology company, announced publication of data of entinostat combined with the demethylating agent Vidaza® (azacitidine) showing effect in reducing tumor burden in differentiated tumor cells in animal tumor models of non-small cell lung cancer (NSCLC).  The data is being published in the January 15, 2011 issue of Cancer Research.

"These findings demonstrate the promise for epigenetic therapy in cancer management and provide us with important new insights to guide further development of human treatments for lung cancer," said Steven Belinsky, Ph.D., vice president for academic research, director, lung cancer program, Lovelace Respiratory Research Institute.  "Epigenetic therapy may circumvent the problem of tumor heterogeneity by inducing the re-expression of multiple tumor suppressor genes essential for abrogating cancer cell survival and proliferation."

The purpose of the study was to determine the efficacy of a demethylating agent, Vidaza, alone or in combination with a histone deacetylase inhibitor (HDACi), entinostat, on the growth of tumors engrafted in the lungs of the nude rat and on reprogramming of the epigenome.  Researchers developed an orthotopic lung cancer model in which xenografts of human lung cancer-derived cell lines are efficiently engrafted throughout the lungs of the nude rat.  The study showed that combining the HDACi entinostat with the demethylating agent Vidaza profoundly affected growth of K-ras/p53 mutant lung adenocarcinomas engrafted orthotopically in immunocompromised nude rats by targeting and ablating pleomorphic cells that occupied up to 75% of the tumor masses.

"These exciting findings of entinostat combined with Vidaza in a validated animal model of lung cancer support ongoing clinical efforts with epigenetic therapy in solid tumors and provide a foundation for identification and  development of patient  selection tools for this novel therapeutic approach," said Joanna Horobin, M.D., president and chief executive officer of Syndax.  "These results have been confirmed in a phase 2 clinical trial of entinostat and Vidaza in patients with advanced NSCLC who had progressed after a median of three prior therapies giving us hope that this combination could become a much needed treatment option in the future for this patient population."

Similar results to the response seen in this orthotopic model were seen in a phase 2 trial of Vidaza and entinostat in heavily pretreated patients with relapsed advanced  NSCLC. Progressive disease was controlled in 10 of 28 evaluable patients, including one complete response, one partial response and eight patients with disease stabilization of at least four months. These results were presented by Dr. Rosalyn Juergens from Johns Hopkins University School of Medicine at the 13th  World Conference on Lung Cancer in 2009.