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
► In vivo models for chemotherapy-induced peripheral neuropathy (CIPN)
► 3D-spheroid tumor micro-environment models (using patient derived cells and tumor microenvironment cellular components)
► Disease models in non-cancer indications
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 tumor-stromal and in vivo tumor models have demonstrated APE1/Ref-1 regulation of a number of important transcription factors including HIF1, NFkB, STAT3 and others.
► Inhibition of APE1/Ref-1 with APX3330 in combination with other agents blocking APE1/Ref-1 confluent pathways have provided synergistic anti-tumor effect in 3D-spheroid tumor-microenvironment models of cancer creating a “drug synthetic lethality” effect.
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. There is currently no effective therapy to prevent or reverse CIPN making it an area of high unmet medical need for cancer patients world-wide. Using state of the art in vivo models, our data indicate that APX3330 protects sensory neurons from developing CIPN without compromising the anti-tumor effect of these drugs and that APX3330 actually reverses existing CIPN.
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. These diseases include malignant peripheral nerve sheath tumors (MPNST), tuberous sclerosis complex (TSC), and age related macular degeneration (AMD), as well as others.