Selective targeting of cancer stem cells
Aspects of the invention relate to methods and related compositions for preferentially targeting cancer stem cells. In some embodiments, the methods utilize PKC-α/FRA1 pathway inhibitors to target carcinoma cells. Also provided are methods for identifying a candidate compound for selectively inhibiting growth of cancer stem cell, and methods for obtaining cells that have undergone an epithelial to mesenchymal transition.
1. A method of treating a subject having a carcinoma, the method comprising
(a) detecting FRA1 using an antibody that specifically binds to FRA1 or detecting RNA encoding FRA1 by performing reverse transcription and quantitative PCR, in a sample obtained from the carcinoma and then;
(b) administering to the subject a therapy effective against non-CSC carcinoma cells; and
(c) administering to the subject an EGFR inhibitor, a sphingosine kinase pathway inhibitor, and/or a PKC-α/FRA1 pathway inhibitor.
2. The method of claim 1 , wherein step (b) comprises administering to the subject a therapy effective against non-CSC carcinoma cells, wherein the therapy comprises radiation therapy, a spindle poison, a DNA replication inhibitor, an alkylating agent, or a platinum-based compound.
3. The method of claim 1 , wherein step (a) comprises detecting FRA1 using an antibody that specifically binds to FRA1.
4. The method of claim 1 , wherein the PKC-α/FRA1 pathway inhibitor is a Protein Kinase C-alpha (PKC-α) inhibitor, wherein the PKC-α inhibitor targets PKC-α.
5. The method of claim 4 , wherein the PKC-α inhibitor is a small interfering nucleic acid comprising a region of complementarity with PKC-α mRNA that inhibits expression of PKC-α protein.
6. The method of claim 5 , wherein the small interfering nucleic acid is an antisense oligonucleotide, miRNA, shRNA or siRNA that targets PKC-α mRNA.
7. The method of claim 1 , further comprising contacting the carcinoma cells with an inhibitor of PKCη, CLK1, CDK6 or JAK1.
8. The method of claim 1 , wherein the PKC-α/FRA1 pathway inhibitor is an inhibitor of PDGFRα or PDGFRβ.
9. The method of claim 8 , wherein the inhibitor of PDGFRα or PDGFRβ is imatinib.
10. The method of claim 1 , wherein the PKC-α/FRA1 pathway inhibitor is a PDGFR neutralizing antibody or PDGFR inhibitor.
11. The method of claim 1 wherein the PKC-α/FRA1 pathway inhibitor is a FRA1 inhibitor.
12. The method of claim 1 , wherein the PKC-α/FRA1 pathway inhibitor is an ERK inhibitor.
13. The method of claim 1 , further comprising contacting the carcinoma cells with an EGFR inhibitor.
14. The method of claim 1 further comprising contacting the cells with a sphingosine kinase pathway inhibitor.
15. The method of claim 14 , wherein the sphingosine kinase pathway inhibitor is a sphingosine kinase 1 inhibitor or sphingosine kinase 2 inhibitor.
16. The method of claim 14 , wherein the sphingosine kinase pathway inhibitor is a sphingosine-1-phosphate receptors 1 and 3 (S1PR1/3) antagonist.
17. The method of claim 1 , wherein the carcinoma cells comprise basal-like breast cancer cells.
18. The method of claim 1 , wherein the carcinoma cells comprise cells arising from the airway epithelium, pancreas ductal epithelium, intestinal epithelium, prostate epithelium or breast epithelium.
19. The method of claim 1 , wherein the carcinoma cells are breast carcinoma cells characterized as Her2neg, ERneg, and PRneg.
20. The method of claim 4 , wherein the PKC-α inhibitor inhibits activity and/or expression of PKC-α.
21. The method of claim 16 , wherein the sphingosine-1-phosphate receptors 1 and 3 (S1PR1/3) antagonist is VPC23019.