Abstract
Background: Cutaneous T-cell lymphoma (CTCL) is a heterogeneous neoplasm and patients with relapsed/refractory disease exhibit resistance to standard cytotoxic therapies. We have previously demonstrated that the MUC1-C oncoprotein plays a critical role in regulating apoptosis and protection from oxidative stress in CTCL. Targeting of MUC1-C with a pharmacologic inhibitor, GO-203, was associated with late apoptosis and early necrosis and slowing of tumor growth in in vitro and in vivo models of CTCL, respectively. However, disease responses following MUC1-C inhibition were incomplete underscoring the need for combinatorial strategies that could exploit the vulnerability of CTCL cells to oxidative signals. Decitabine is a DNA methyltransferase inhibitor, previously shown to modulate oxidative stress in acute myeloid leukemia models. We hypothesized that treatment with decitabine and GO-203 would present a potent novel therapeutic combination for patients with CTCL.
Method/Results: Our studies demonstrate that exposure of CTCL cells to decitabine in combination with GO-203, increased the generation of reactive oxygen species (ROS) and decreased levels of scavenger molecules, NADPH, glutathione (GSH), and TIGAR, a p53-inducible regulator of glycolysis and apoptosis, critical to intracellular redox homeostasis. This in turn led to marked increase in the ratio of stress activated proteins; phospho-p38 and phospho-JNK to Total-p38 and Total-JNK repectively. Further dual exposure to GO-203 and decitabine resulted in near abrogation of DNA methyl transferase 1 and 3b crucial for maintaining DNA methylation, demonstrating significant synergy of these agents for inducing hypomethylation. In concert with these findings, treatment with decitabine and GO-203 upregulated the ROS generating enzyme, NADPH oxidase 4 (Nox4) potentially due to their effect on epigenomic regulation of this protein. In concert with these findings, exposure to decitabine and GO-203 resulted in heightened apoptotic death of CTCL cell lines, primary patient derived samples and in a aggressive murine xenograft model.
Conclusion: These findings indicate that decitabine augments MUC1-C inhibition induced redox imbalance and provides a novel combination of targeted and epigenetic agents for treatment of patients with CTCL. Accordingly an early phase multi-institution clinical trial to to investigate this combinatorial strategy based on epigenetic modulation of redox homeostasis in patients with relapsed/refractory T cell lymphomas is being planned.
Disclosures
Rosenblatt: Astex: Research Funding; BMS: Research Funding; DCPrime: Research Funding. Arnason:Gilead: Consultancy. Kufe:Genus Oncology LLC: Consultancy, Equity Ownership.
889 Interleukin-9 promotes malignant T cell survival by inhibiting oxidative stress and lactic acidosis in cutaneous T cell lymphoma
