Preclinical Models: APX3330 is a targeted inhibitor of the APE1/Ref-1 protein. APX3330 single-agent effect has been tested in a broad variety of disease models including:
► Over 27 cancer cell lines (in vitro established cell lines, co-cultures and patient derived tumor cells)
► In vivo xenograft and orthotopic models, including orthotopic models of metastasis and tumor-stromal cell-containing models
► Over 10 disease models in non-cancer indications (e.g., inflammation, chemotherapy-induced peripheral neuropathy/CIPN, angiogenesis)
► Genetically engineered mouse models
► 3D-spheroid models (using patient derived cells and cancer associated fibroblasts)
Combination and single-agent studies: We have conducted combination and single agent pre-clinical studies:
► Published and internal data on APX3330 usage in 3D spheroid and in vivo tumor models has demonstrated Ref-1 regulation of STAT3, a member of the JAK-STAT3 signaling pathway. Pre-clinical studies of ruxolitinib combined with APX3330 have provided synergistic anti-tumor effect in 3D-spheroid models of pancreatic cancer, indicating the importance of continued testing of APX3330 in combination with JAK/STAT pathway inhibitors
► Single-agent APX3330 dramatically reduces immune cell production of IL-6, with a concomitant reduction in IL-6-receptor binding
► Recently published data using in vivo eye models for age-related macular degeneration (AMD) and neo-vascular diseases indicate additive benefit when combining APX3330 with bevacizumab
Planned tests include additional evaluation of APX3330 in combination with CAIX inhibitors
Other diseases: Given APX3330’s targeted effect on the APE1/ref-1 protein, research is focused on understanding its effect on diseases in which the HIF, STAT3 or NFkB pathways are a major driving force, not only including APE1-over expressing tumors, but also AMD via pathways involving HIF and NFkB, malignant peripheral nerve sheath tumors driven by STAT3 and HIF, and other diseases.
CIPN studies: Chemotherapy-induced peripheral neuropathy (CIPN) is one of the most debilitating side effects of anti-cancer therapy. Indeed, anti-cancer drugs used for the six most common malignancies pose a substantial risk for CIPN. These drugs include, but are not limited to platinum agents, taxanes, vinca alkaloids, proteasome inhibitors, targeted therapeutic agents and even new, immune-modulators. Clearly, the development of therapies to prevent or reverse CIPN is of critical importance to cancer patients world-wide. Our data indicates that APX3330 protects sensory neurons from the oxidative DNA-damaging effects of radiation and chemotherapy without compromising the anti-tumor effect of these drugs.