Augmenting chemotherapy with low-dose decitabine through an immune-independent mechanism

The DNA Methyltransferase Inhibitor decitabine has classically been used to reactivate silenced genes and as a pre-treatment for anti-cancer therapies. In a new variation of this idea, this study explores the concept of adding low-dose decitabine following administration of chemotherapy to bolster therapeutic efficacy. We find that addition of decitabine following treatment with the chemotherapy gemcitabine improves survival and slows tumor growth in a mouse model of high-grade sarcoma. Unlike prior studies in epithelial tumor models, low-dose decitabine did not induce a robust anti-tumor T cell response in sarcoma. Furthermore, low-dose decitabine synergizes with gemcitabine independently of the immune system. Mechanistic analyses demonstrate that the combination therapy induces bi-phasic cell cycle arrest and Apoptosis. Therapeutic efficacy was found to be sequence dependent, with gemcitabine priming cells for treatment with decitabine through inhibition of ribonucleotide reductase. This study identifies a unique application of low-dose decitabine to augment the cytotoxic effects of conventional chemotherapy in an immune-independent manner. The concepts explored in this study represent a promising new paradigm for Cancer treatment by augmenting chemotherapy through addition of low-dose decitabine to increase tolerability and improve patient response. These findings have widespread implications for the treatment of sarcomas and Other aggressive malignancies.

Cancer; Drug therapy; Mouse models; Oncology.