Using a novel NQO1 bioactivatable drug beta-lapachone (ARQ761) to enhance chemotherapeutic effects by metabolic modulation in Pancreatic Cancer

摘要

Novel, tumor-selective therapies are needed to increase the survival rate of pancreatic cancer patients. K-Ras-mutant-driven NAD(P)H:quinone oxidoreductase 1 (NQO1) is over-expressed in pancreatic tumor vs associated normal tissue, while catalase expression is lowered compared to levels in associated normal pancreas tissue. ARQ761 undergoes a robust, futile redox cycle in NQO1+ cancer cells, producing massive hydrogen peroxide (H2O2) levels; normal tissues are spared by low NQO1 and high catalase expression. DNA damage created by ARQ761 in pancreatic cancer cells ‘hyperactivates’ PARP1, causing metabolic catastrophe and NAD+-keresis cell death. NQO1: catalase levels (high in tumor, low in normal tissue) are an attractive therapeutic window to treat pancreatic cancer. Based on a growing body of literature, we are leading a clinical trial to evaluate the combination of ARQ761 and chemotherapy in patients with pancreatic cancer.