EPICA

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.