Pancreatic cancer is the fourth leading cause of cancer-related deaths. As the disease progresses, cancer cells travel (metastasize) from the pancreas to other parts of the body. Despite substantial improvements in cancer patient survival, metastatic diseases remain ineffectively treated. The majority of pancreatic cancer patients are diagnosed only after the cancer has spread, and nearly all patients succumb to the metastatic burden. These researchers have identified both a cellular target that is prevalent in metastatic cancer cells and a compound that inhibits the metastatic process. The aim of this project is to continue to develop this therapy to prepare it for human trials.
The perinucleolar compartment (PNC) is a subcellular structure whose formation closely associates with metastatic potential of cancer cells. The PNC, which is located at the nucleolar periphery, is a dynamic subnuclear body enriched with RNA transcripts and RNA-binding proteins. It is highly prevalent in metastatic tumors, metastatically transformed cancer cell lines, and 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. Metarrestin shows anti-oncogenic properties in vitro, including inhibition of migration and invasion. It demonstrates desirable pharmacokinetic properties and bioavailability, and in an animal model of pancreatic metastasis, it significantly reduced metastatic burden in the lung and liver and extended survival.
National Cancer Institute, Bethesda, MD
Udo Rudloff, M.D., Ph.D.
Public Health Impact
An estimated 54,000 people will be diagnosed with pancreatic cancer in 2017, with an overall five-year survival rate of only 5 percent to 7 percent. Most cases are diagnosed after the cancer has progressed to an advanced stage, where the metastatic burden is high. However, even with early detection and treatment, there is near universal recurrence due to systemic metastasis. Therapy that can affect metastatic progression may improve the outcome for patients at all stages of disease.
BrIDGs program scientists completed formulation development, manufacture of Good Manufacturing Practice (GMP) drug product, and pharmacokinetic and IND-directed toxicology studies. As a result of BrIDGs support, an IND was cleared by the FDA, allowing the collaborator to initiate clinical trials. See ClinicalTrials.gov, NCT04222413.