Abstract
PurposeMetarrestin is a first-in-class small molecule clinical candidate capable of disrupting the perinucleolar compartment, a subnuclear structure unique to metastatic cancer cells. This study aims to define the pharmacokinetic (PK) profile of metarrestin and the pharmacokinetic/pharmacodynamic relationship of metarrestin-regulated markers.MethodsPK studies included the administration of single or multiple dose of metarrestin at 3, 10, or 25 mg/kg via intravenous (IV) injection, gavage (PO) or with chow to wild-type C57BL/6 mice and KPC mice bearing autochthonous pancreatic tumors. Metarrestin concentrations were analyzed by UPLC–MS/MS. Pharmacodynamic assays included mRNA expression profiling by RNA-seq and qRT-PCR for KPC mice.ResultsMetarrestin had a moderate plasma clearance of 48 mL/min/kg and a large volume of distribution of 17 L/kg at 3 mg/kg IV in C57BL/6 mice. The oral bioavailability after single-dose (SD) treatment was > 80%. In KPC mice treated with SD 25 mg/kg PO, plasma AUC0–∞ of 14400 ng h/mL, Cmax of 810 ng/mL and half-life (t1/2) of 8.5 h were observed. At 24 h after SD of 25 mg/kg PO, the intratumor concentration of metarrestin was high with a mean value of 6.2 µg/g tissue (or 13 µM), well above the cell-based IC50 of 0.4 µM. At multiple dose (MD) 25 mg/kg/day PO in KPC mice, mean tissue/plasma AUC0–24h ratio for tumor, spleen and liver was 37, 30 and 31, respectively. There was a good linear relationship of dosage to AUC0–24h and C24h. AUC0–24h MD to AUC0–24h SD ratios ranged from two for liver to five for tumor indicating additional accumulation in tumors. Dose-dependent normalization of FOXA1 and FOXO6 mRNA expression was observed in KPC tumors.ConclusionsMetarrestin is an effective therapeutic candidate with a favorable PK profile achieving excellent intratumor tissue levels in a disease with known poor drug delivery.
Highlights
Despite metastatic disease dissemination being the main cause of cancer-related mortality, there is a disproportionate paucity of successful drug development efforts selectively targeting metastasis [1,2,3]
There are various well characterized key processes and signal transduction pathways involved in metastatic colonization such as transcriptional programs induced by snail family transcriptional repressor 1 (SNAI1), inhibitor of DNA binding 1 (ID1), GATA-binding protein (GATA3), EMT, upregulated autocrine interleukin-6 (IL-6)-signal transducer and activator of transcription 3 (STAT3) signaling, or dysregulation of exosome formation and expression of various non-coding RNAs, these perturbations are either difficult to target, have redundant parallel signaling routes, are essential for normal tissue homeostasis, or are not selective for the evolved, metastatic disease stage [4]
The perinucleolar compartment (PNC) is a small subnuclear organelle located adjacent to the nucleolus [5,6,7]
Summary
Despite metastatic disease dissemination being the main cause of cancer-related mortality, there is a disproportionate paucity of successful drug development efforts selectively targeting metastasis [1,2,3]. PNC prevalence (the presence of one or more PNC structures per cell) correlates in various in vitro and in vivo cancer models, as well as in patient-derived clinical samples with the evolvement of malignant progression [10]. In correlative tissue studies of clinical samples from patients with breast, colon, and ovarian cancer PNC prevalence is both a strong predictive and prognostic marker of overall patients clinical outcome including overall survival [7, 11, 12]. The PNC is an attractive marker for drug development efforts targeting the metastatic disease state (Fig. 1a)
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