The promise of DNA methyltransferase inhibitors for the treatment of triple negative breast cancer

In cancer, loss of gene expression occurs about 10 times more frequently because of hypermethylation than mutations. Hypermethylation can inhibit genes that prevent cancer formation and genes responsible for an antitumor immune response, and is particularly common in triple negative breast cancer (TNBC). The reversibility of these covalent modifications makes them attractive targets for therapeutic intervention.

There are two approved DNA methyltransferase (DNMT) inhibitors for the treatment of hematologic malignancies, 5-azacytidine and decitabine. Unfortunately, these two drugs have not yet demonstrated efficacy in the treatment of breast cancer (BC). iMN013 is a nucleoside that has a base identical to decitabine and 5-azacytidine that confers DNMT inhibition, leading to the expression of hypermethylated genes. The sugar is identical to that of gemcitabine, a drug approved for the treatment of metastatic BC that inhibits ribonucleotide reductase, a critical target for TNBC survival. iMN013 is active against BC cell lines in the nM range.

The prodrug of iMN013, iMN041 was demonstrated to be an immunotherapeutic in a syngeneic tumor             mouse model with significant increases in granzyme B in NK and NKT cells, and in the ratios of CD8-T to regulatory T cells (Treg) and CD4-T to Treg cells while inhibiting myeloid-derived suppressor cells, compared to vehicle controls. Decreased numbers of Treg cells were noted in iMN041 treated animals, differing from decitabine which has been shown to stimulate an increase in Treg cells. A significant decrease in MAGE-A positive tumor cells in iMN041 treated mice suggests that these cells are one of the main targets of the activated immune system. Mage-A is frequently elevated in TNBC. iMN041 was effective in mouse xenograft models of solid tumors, including non-small cell lung, pancreatic, renal and TNBC. In the TNBC model (cell line DU4475), iMN041 demonstrated significant inhibition of tumor growth and improved survival of treated mice compared to vehicle control.

iMN041 raises the possibility of treating TNBC patients with a more effective and less toxic regimen that will favorably impact survival by derepressing genes, such as the tumor suppressor TP53, resulting in tumor cell apoptosis, and by stimulating of the patient’s own anti-tumor immune response.