Abstract 4653: Combination Azacitidine and histone deacetylase inhibition induces a multi factorial synergistic anti-tumor response in non-small cell lung cancer (NSCLC)

Proceedings: AACR 107th Annual Meeting 2016; April 16-20, 2016; New Orleans, LA Epigenetic therapy holds much promise as an emerging paradigm for the treatment of many disparate types of human cancer. However, the data in solid malignancies, particularly, would suggest further optimization is required to extract the true potential of these therapies. In our current study, we have deployed at low, clinically achievable doses, chronic combinatorial administration of the DNA methyltransferase inhibitor Azacitidine in conjunction with both benzamide and hydroxyamic acid based histone deacetylase inhibitors (HDACi) in NSCLC. We have developed our paradigms by sequentially employing chronic HDACi administration after Azacitidine. This strategy achieves durable alteration of the cell transcriptome with corresponding induction of both cell cycle arrest and apoptosis. These events appear driven by alterations, both transcriptionally and post transcriptionally of Myc and Myc regulatory proteins. Epigenetic treatment induced perturbation of Myc is facilitated by Wnt pathway inhibition through induction of Wnt antagonists, namely DKK proteins. Importantly, as part of this scenario of altering a Myc regulatory axis, there is a synergistic cytotoxic response mediated at least in part through downregulation of a critical effector, the Skp2 oncogene. Additionally, we observe significant induction of an interferon responsive viral defense gene signature as the result of epigenetic treatment. This gene signature has been shown to correlate with response to immune checkpoint blockade in the setting of metastatic melanoma. We propose that this combination of viral defense gene signature augmentation in conjunction with potent direct epithelial cancer cytotoxicity holds promise to be a more complete therapeutic paradigm for the treatment of NSCLC. Citation Format: Michael Topper, Christin Hanigan, Michelle Vaz, Katherine Chiappinelli, Julin Justin, Lauren Murphy, Cynthia Zahnow, Stephen Baylin. Combination Azacitidine and histone deacetylase inhibition induces a multi factorial synergistic anti-tumor response in non-small cell lung cancer (NSCLC). [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4653.