Background/rationale: Epigenetic modifications are implicated in a variety of diseases including cancer. Thus, its modulation by using inhibitors of DNA methyltransferases (DNMT) or histone deacetylases have been developed and proved efficacious against cancer.
Recent evidence further suggests that these drugs have immunomodulatory properties and synergize with immunotherapy, representing another major breakthrough in cancer therapy. We developed novel compounds that simultaneously inhibit the activity of the histone methyltransferase G9a and DNMT1, showing a potent in vitro and in vivo activity against a wide range of cancers. These inhibitors also promote a pro-inflammatory signature, which might favor anti-tumor immunity.
Hypothesis: Combination of the newly defined epigenetic drugs with immunotherapeutic strategies represents a novel targeted chemo-immunotherapy approach with synergistic effects against cancer.
Aims:
1) To study the molecular events underlying the anti-tumor and immunomodulatory activities of the newly defined G9a/DNMT1 dual inhibitor (CM272) in vitro and in vivo in comparison with approved hypomethylating agents.
2) To develop a novel combinatorial strategy with state-of-the art immunotherapies leading to a first-in-man clinical study.
Methods: Antitumor effect of CM272 will be tested in murine tumor models, alone or combined with vaccines, checkpoint inhibiting antibodies or adoptive T cell therapy. Immune cell subsets (effector T cells, Treg cells, and antigen presenting cells) will be studied over the course of treatment and tumor debulking on sorted populations by gene expression analysis, flow cytometry and functional assays.
Expected results and potential impact: Preclinical data will help elucidate anti-tumor and immunomodulatory effects of the newly designed dual epigenetic drug and define novel combinatorial strategies suitable for clinical application. Efficacy and safety will be determined to design a first-in-man-clinical study.