Robyn Boyle, RPh, for MDLinx | June 05, 2018
A new experimental drug called metarrestin suppressed development of metastasis and extended survival in mouse models of pancreatic, prostate, and breast cancers. The study was published in Science Translational Medicine.
Metarrestin appears to work by killing cells that have developed a structure called the perinucleolar compartment (PNC) within their nuclei. These structures develop almost exclusively in metastatic cancer cells. In addition, PNC prevalence is linked to increased metastatic potential, disease progression, and poor outcomes.
The goal of the study, led by Kevin J. Frankowski, PhD, now a research assistant professor at the University of North Carolina at Chapel Hill, was to develop and validate an approach to identify effective compounds to prevent metastasis.
Using PNCs as a phenotypic marker of the metastatic behavior of cancer cells, researchers assessed compounds that disrupted the marker and interfered with the metastatic process.
To screen for small molecules that disassemble PNCs, the team engineered a metastatic prostate cancer cell line that identified a compound—later named metarrestin—that reduced PNC prevalence in the cells and could block metastasis.
Next, the compound was tested in a mouse model of pancreatic cancer that closely mimics the growth of the cancer in humans and which has high PNC prevalence in metastatic tumors.
Metarrestin treatment reduced the PNCs in metastatic tumor cells of mice and more than doubled overall survival. Mice treated with metarrestin were free of metastases in the lung and liver, while untreated mice (n=10 in each cohort) had metastatic tumors in the liver (P < 0.01) and lungs (P < 0.05).
Moreover, the treatment was well tolerated, as there was no apparent impact on body weight of the mice. In addition, the treated mice remained agile and well-groomed when compared to untreated mice.
"There was no significant difference in primary tumor growth in the pancreas between treated and untreated animals," the researchers wrote. “These findings suggest a survival gain due to suppression of metastasis-related death.”
A patient-derived breast cancer xenotransplantation model (PDX) was used to evaluate the effect of metarrestin on a malignant xenograft considered closest to in vivo conditions. Metarrestin effectively inhibited the PDX growth.
The investigators assessed cellular changes during metarrestin treatment, and determined that it works by disrupting the nucleolar structure and inhibits RNA polymerase transcription.
“Metarrestin is a small molecule which is selective against metastasis across different preclinical cancer histologies, with high intratumoral exposure and without appreciable toxicity,” concluded the authors, who propose that it is a promising approach to treat metastatic cancer.
To read more about this study, click here.