Metarrestin for the Treatment of Pancreatic Cancer

National Center For Advancing Translational Sciences

Investigators

Abstract

The perinucleolar compartment (PNC) is a subcellular structure whose formation closely associates with metastatic potential of cancer cells. PNCs are located at the nucleolar periphery, and are dynamic subnuclear bodies enriched with RNA transcripts and RNA-binding proteins. The PNC is highly prevalent in metastatic tumors, metastatically transformed cancer cell lines, and in cancer stem cells. It is rarely found in normal cells, including human embryonic stem cells. A high PNC prevalence positively correlates with disease progression (stages and grades) in tested primary tumors, including breast, colorectal and ovarian cancers, and inversely correlates with patient outcomes. Current evidence indicates that PNC prevalence reflects the metastatic capability of a given cellular population derived from solid tissue origins. Reduction of PNC prevalence was used as a phenotypic marker to screen for compounds that interfere with cellular mechanisms essential for the metastatic capability of cancer cells. This led to the discovery of a compound that was further optimized in a medicinal chemistry campaign to produce metarrestin, a compound that reduces PNC prevalence in multiple cell lines without significant impact on cell viability. It shows anti-oncogenic properties in vitro, including inhibition of migration and invasion. Metarrestin demonstrates desirable pharmacokinetic properties and bioavailability, and in an animal model of pancreatic metastasis, metarrestin significantly reduced metastatic burden in the lung and liver and extended survival. The BrIDGs team is collaborating on the completion of the following studies for metarrestin: - Formulation development - Method development for analysis of Good Manufacturing Practice (GMP) material - Manufacture of GMP drug product - Bioanalytical method development - Stability studies - Investigational New Drug (IND)-directed toxicology