ER-stress inducing compounds and methods of use thereof
View Patent ↗The invention relates to methods for identifying ER-stress inducing compounds that target cancer stem cells. In some aspects, the invention relates to treatment methods that use ER-stress inducing compounds that specifically target cancer stem cells for inhibiting the growth and/or survival of cancer stem cells in a subject in need thereof. Other aspects of the invention relate to the use of cancer stem cell biomarkers in the selection of a treatment for inhibiting the growth and/or survival of cancer stem cells in a subject in need thereof.
1. A method of selecting a treatment for a subject having a carcinoma, the method comprising:
conducting an assay to determine the extent of UPR signaling in cells of the carcinoma, wherein, if the extent of UPR signaling in the cells of the carcinoma is higher than the extent of UPR signaling in cells from normal epithelium, then an ER-stress inducing compound is suitable for treating the subject, and if the extent of UPR signaling in the cells of the carcinoma is equal to or less than the extent of UPR signaling in cells from normal epithelium, then an ER-stress inducing compound is not suitable for treating the subject; and
selecting a treatment for the subject based at least in part on the results of the assay.
2. The method of claim 1 , wherein the extent of UPR signaling in the cells of the carcinoma is higher than the extent of UPR signaling in cells from normal epithelium, and the method further comprises treating the subject with an ER-stress inducing compound based on the results of the assay.
3. The method of claim 1 , wherein the cells of the carcinoma are cancer stem cells.
4. The method of claim 1 , wherein the extent of UPR signaling is directly related to the secretory load on the cells.
5. The method of claim 1 , wherein conducting an assay to determine the extent of UPR signaling comprises measuring activity of the PERK signaling pathway.
6. The method of claim 1 , wherein conducting an assay to determine the extent of UPR signaling comprises measuring activity of the IRE1a signaling pathway.
7. The method of claim 1 , wherein conducting an assay to determine the extent of UPR signaling comprises measuring activity of the ATF6 signaling pathway.
8. The method of claim 1 , wherein conducting an assay to determine the extent of UPR signaling comprises measuring phosphorylation of eIF2α as an indicator of activity of the PERK signaling pathway, measuring splicing of XBP1 mRNA as an indicator of activity of the IRE1a signaling pathway, or measuring nuclear translocation of ATF6 as a marker of the ATF6 signaling pathway, or a combination thereof.
9. The method of claim 1 , wherein conducting an assay to determine the extent of UPR signaling comprises measuring expression of CHOP, Bip, calnexin or GRP94.
10. The method of claim 1 , wherein conducting an assay to determine the extent of UPR signaling comprises measuring activity of one or more UPR signaling pathways in cells of the carcinoma and determining that the activity of at least one of the UPR signaling pathways in cells of the carcinoma is higher than the activity of such UPR signaling pathway(s) in normal epithelium; and selecting a method of treatment comprises selecting an ER-stress inducing compound as a treatment for the subject.
11. The method of claim 10 , wherein conducting an assay to determine the extent of UPR signaling comprises measuring activity of two or more UPR signaling pathways in cells of the carcinoma and determining that only a subset of UPR signaling pathways are active in the cells, and the method further comprises utilizing one or more of the other UPR signaling pathways as a biomarker of the responsiveness of the carcinoma to the treatment.
12. The method of claim 11 , wherein utilizing a UPR signaling pathway as a biomarker of the responsiveness of the carcinoma to the treatment comprises measuring the activity of the UPR signaling pathway in cells of the carcinoma after treatment with the compound and comparing the level of activity with the level of activity prior to treatment, wherein an increase in activity of the pathway as compared to the level of activity before treatment is indicative of responsiveness of the carcinoma to the compound.
13. The method of claim 11 , wherein the method comprises determining that PERK signaling is active prior to the treatment, and the method further comprises measuring the activity of of IRE1a, IRE1b and/or ATF6 signaling pathways as biomarkers of responsiveness.
14. The method of claim 11 , wherein the method comprises determining that IRE1a signaling is active prior to the treatment, and the method further comprises measuring the activity of PERK, IRE1b and/or ATF6 signaling pathways as biomarkers of responsiveness.
15. The method of claim 11 , wherein the method comprises determining that IRE1b signaling is active prior to the treatment, and the method further comprises measuring the activity of PERK, IRE1a and/or ATF6 signaling pathways as biomarkers of responsiveness.
16. The method of claim 11 , wherein the method comprises determining that ATF6 signaling is active prior to the treatment, and the method further comprises measuring the activity of PERK, IRE1a and/or IRE1b signaling pathways as biomarkers of responsiveness.