Therapeutics: DNA (cytosine-5-)-methyltransferase 1 (DNMT1)

Patient sample, cell culture and mouse studies suggest inhibiting DNMT1 could help treat pancreatic ductal adenocarcinoma (PDAC). In patient tumor samples, levels of DNMT1 mRNA were higher in cancer stem cells (CSCs) than in non-CSCs. In a human PDAC cell line, DNMT1 knockout decreased expression of cancer stem cell markers and sphere formation compared with normal DNMT1 expression. In patient-derived PDAC cells, a DNMT1 inhibitor tool compound or Dacogen decitabine decreased proliferation and levels of stem cell markers and proliferation markers compared with vehicle. In a patient-derived xenograft mouse model of PDAC, pretreatment of tumor cells with the tool compound decreased tumor number compared with vehicle pretreatment. Next steps could include testing DNMT1 inhibitors to treat existing PDAC tumors.

Otsuka Pharmaceutical Co. Ltd., Eisai Co. Ltd. and Johnson & Johnson market Dacogen, a hypomethylating agent that inhibits DNA methyltransferase, to treat myelodysplastic syndrome (MDS), and have the compound approved to treat acute myelogenous leukemia (AML) and in Phase I testing to treat ovarian cancer. ...