Methods of treating fibroblast growth factor 19-mediated cancers and tumors
Provided are methods of treating a FGF19-mediated cancer or tumor in a subject by administering to the subject an anti-IL-6 antibody or an anti-IL-6 receptor antibody or an inhibitor of STAT3/JAK signaling pathway, and pharmaceutical compositions relating thereto.
1. A method of treating the initiation or progression of a fibroblast growth factor 19 (FGF19)-mediated cancer or tumor without impacting FGF19-mediated bile acid metabolism in a subject in need thereof, comprising, administering to the subject a therapeutically effective amount of an anti-interleukin-6 (anti-IL-6) antibody, wherein the FGF19-mediated cancer or tumor is a liver cancer or tumor.
2. The method of claim 1 , wherein the anti-IL-6 antibody is siltuximab, clazakizumab, elsilimomab, or sirukumab.
3. The method of claim 1 , wherein the anti-IL-6 antibody is siltuximab, and wherein the dose of the siltuximab (i) is in the range of about 0.1 to 100 mg/kg per day; (ii) is in the range of about 5 to about 25 mg/kg/day; (iii) is about 5 mg/kg per day; (iv) is about 10 mg/kg per day; (v) is about 11 mg/kg per day; or (vi) is about 15 mg/kg per day.
4. The method of claim 1 , wherein the anti-IL-6 antibody is siltuximab, and wherein the siltuximab is administered once every 3 or 4 weeks by intravenous infusion.
5. The method of claim 1 , wherein the administration treats the cancer or tumor without substantially affecting the metabolic function mediated by FGF19.
6. The method of claim 5 , wherein the metabolic function is the ability to regulate bile acid synthesis, glucose metabolism or energy homeostasis.
7. The method of claim 1 , wherein the liver cancer or tumor is a hepatocellular carcinoma (HCC).
8. The method of claim 1 , wherein the expression level of FGF19 or at least one STAT3 target gene is amplified in the cancer or tumor as compared to a control.
9. The method of claim 8 , wherein the at least one STAT3 target gene is BIRC5, BCL2, HSPA4, BCL2L1, or MCL1.
10. The method of claim 8 , wherein the expression level of the FGF19 or the at least one STAT target gene is determined by Quantitative Polymerase Chain Reaction (qPCR), Real-Time Polymerase Chain Reaction (RT-PCR), RNA-seq, Microarray, Serial Analysis of Gene Expression (SAGE), MassARRAY technique, or Fluorescence In Situ Hybridization (FISH), an immunohistochemistry (IHC) assay, an immunoblotting (IB) assay, flow cytometry (FACS), or Enzyme-Linked Immunosorbent Assay (ELISA).
11. A method of modulating FGF19 signaling in a liver cancer cell or liver tumor cell, the method comprising contacting the cell with an anti-IL-6 antibody, thereby reducing FGF19-mediated oncogenic signaling without impacting FGF19-mediated bile acid metabolism in the liver cancer cell or liver tumor cell.