ABSTRACT
Abstract Background The WNT pathway regulates intestinal stem cells and is frequently disrupted in intestinal adenomas. The pathway contains several potential biotargets for interference, including the poly-ADP ribosyltransferase enzymes tankyrase1 and 2. LGR5 is a known WNT pathway target gene and marker of intestinal stem cells. The LGR5+ stem cells are located in the crypt base and capable of regenerating all intestinal epithelial cell lineages. Results We treated Lgr5-EGFP-Ires-CreERT2;R26R-Confetti mice with the tankyrase inhibitor G007-LK for up to 3 weeks to assess the effect on duodenal stem cell homeostasis and on the integrity of intestinal epithelium. At the administered doses, G007-LK treatment inhibited WNT signalling in LGR5+ stem cells and reduced the number and distribution of cells traced from duodenal LGR5+ stem cells. However, the gross morphology of the duodenum remained unaltered and G007-LK-treated mice showed no signs of weight loss or any other visible morphological changes. The inhibitory effect on LGR5+ stem cell proliferation was reversible. Conclusion We show that the tankyrase inhibitor G007-LK is well tolerated by the mice, although proliferation of the LGR5+ intestinal stem cells was inhibited. Our observations suggest the presence of a tankyrase inhibitor-resistant cell population in the duodenum, able to rescue tissue integrity in the presence of G007-LK-mediated inhibition of the WNT signalling dependent LGR5+ intestinal epithelial stem cells.
Subject(s)
Animals , Male , Mice , Stem Cells/drug effects , Sulfones/pharmacology , Triazoles/pharmacology , Tankyrases/antagonists & inhibitors , Receptors, G-Protein-Coupled/drug effects , Cell Proliferation/drug effects , Duodenum/drug effects , Intestine, Small/drug effects , Sulfones/pharmacokinetics , Triazoles/pharmacokinetics , Immunohistochemistry , Mice, Transgenic , Fluorescent Antibody Technique , Microscopy, Confocal , Tankyrases/pharmacology , Tankyrases/pharmacokinetics , Receptors, G-Protein-Coupled/genetics , Duodenum/cytologyABSTRACT
CONTEXT: Rigosertib, a potent, multi-kinase inhibitor that selectively induces mitotic arrest and apoptosis in cancer cells and is non-toxic to normal cells, is being developed for the treatment of solid tumors and hematological malignancies. AIMS: To determine the safety, doselimiting toxicities, and clinical activity of rigosertib administered by 2-, 4-, or 8-hour continuous IV infusion twice-a-week for 3 weeks out of a 4-week cycle in patients with advanced solid tumor or hematological malignancies; and to confirm the safety and tolerability of the recommended phase 2 dose (RPTD). SETTINGS AND DESIGN: Phase 1, open-label, dose-escalation study in men and women ≥18 years of age. MATERIALS AND METHODS: An escalation phase optimized the duration of infusion (2, 4, or 8 hours) of 3200 mg rigosertib twice-a-week for 3 weeks of a 4-week cycle; an expansion phase confirmed the maximum tolerated dose (MTD). STATISTICAL ANALYSIS USED: All data summaries were descriptive. PK parameters were estimated using compartmental analysis. RESULTS: 25 patients (16 male, 9 female, 26- 66 years, all Asian) were treated with rigosertib, 16 in the escalation phase; 9 in the expansion phase. MTD was determined to be 3200 mg as a 4-hour infusion and 2400 mg over 4 hours was declared to be the RPTD. Best response was stable disease in 5 of 14 evaluable patients, with a mean (range) of 90 (43-108) days. CONCLUSIONS: 2400 mg rigosertib as a 4-hour infusion was identified as the RPTD. Five patients achieved stable disease lasting 6-16 weeks.