The mortality of certain cancer subtypes, including pancreatic cancer, remains disproportionately high due to the lack of effective treatment against metastasis, the primary cause of death in these patients. To target metastasis, a complex problem without clear understanding of the mechanism, we have developed an alternative top-down approach where we identified a cytological marker (perinucleolar compartment, PNC), which we believe could reflect the malignant behavior of cancer cells more comprehensively than a single gene or gene products. The formation of PNCs closely associates with the metastatic potential of cancer cells in vitro and in vivo. PNCs, located at the nucleolar periphery, are dynamic subnuclear bodies enriched with RNA transcripts and RNA-binding proteins. PNCs are highly prevalent in metastatic tumors, transformed cancer cell lines, and in cancer stem cells. We believe that PNC prevalence could be a phenotypic marker reflecting metastasis. Using this marker as a surrogate phenotypic marker, we have developed a high-content screen against PNC, to screen for compounds that interfere with cellular mechanisms essential for the metastatic capability of cancer cells. Optimization of one hit generated metarrestin, a first in class compound that disrupts the PNC with an IC50 around 300 nM. Metarrestin effectively inhibits metastasis in three murine models of human cancers, including pancreatic, prostate and breast cancers without significant adversary effect in treated animals. The inhibition of metastasis makes metarrestin a useful molecular probe and lead chemotherapeutic candidate. In this proposal, we will focus on two objectives: (1) we will prepare new probes based on the structure of metarrestin to improve potency/selectivity and lack of ability to penetrate blood-brain barrier; (2) we will optimize other screening hits through multiple in vitro and in vivo assay to validate the variants for their in vivo efficacy against metastasis.
|Effective start/end date||9/28/20 → 5/31/22|
- University of North Carolina at Chapel Hill (Agmt 9/28/2020)