(497f) Synergistic Combinations Using APE1 Inhibitors for Ablation of Advanced Melanoma

Cancer is a debilitating disease which is diagnosed in nearly 1.7 million Americans each year. Nearly 200,000 of these are attributed to bladder(4^th common), skin (5^th common) and ovarian Cancer (7^th common). These cancers result in the death of 40,000 people annually in the United states of America. A popular strategy to overcome these cancers has been the use of small molecules to inhibit the molecular chaperone heat shock protein 90(HSP90), which protects cancer cells from multiple forms of environmental stress through its ability to regulate a multitude of signaling and growth pathways. Unfortunately, the in-vitro efficacy of targeting HSP90 has not translated well into the clinic with the most promising results shown in breast and lung cancer. This is mostly attributed to resistance mechanisms developed due to expression of proteins like HSP70, HSP27 and HSF-1. Here we show a novel combination of inhibitors of HSP90 and APE1, A DNA repair/redox function protein which led to synergistic cell death in several cancer cells both using 2d proliferating and 3D dormant cell cuture systems. The combination treatment induced a significant drop in mitochondrial membrane potential and significant increase in Reactive oxygen species(ROS) generation respectively. Based on our hypothesized mechanism we measured change in expression of proteins like PTEN, NF-ƘB, AP-1 etc post combination treatment and were able to observe a significant change in expression levels. The Combination treatment demonstrated significant reduction in growth of aggressive human melanoma tumors, containing both BRAF V600E and NRAS Q61K mutations, in NOD SCID gamma mice compared to single agent treatments acting alone. The treatment also significantly abrogated metastasis of cancer cells to the lungs and liver compared to individual treatments acting alone. Our results indicate that the synergistic inhibition of APE1 and HSP90 proteins is a promising combination treatment for ablation of aggressive tumors.