Compositions and methods for treatment of glioma
In certain embodiments the present invention provides methods useful in the treatment of glioma, such as glioblastoma, such methods comprising administering to a subject in need thereof a CSF-IR inhibitor together with one or more additional active agents such as IGF-IR inhibitors, PI3K inhibitors, IL4 inhibitors, NFAT inhibitors, and/or Stat6 inhibitors. In certain embodiments the present invention provides pharmaceutical compositions comprising a CSF-IR inhibitor together with one or more of such additional active agents.
1. A method of treating CSF-1R inhibitor resistant glioma, the method comprising administering to a mammalian subject with a CSF-1R inhibitor resistant glioma an effective amount of: (a) a CSF-1R inhibitor, and (b) an IGF-1R inhibitor or a PI3K inhibitor, thereby treating the CSF-1R inhibitor resistant glioma.
2. The method of claim 1 , comprising administering to the subject an effective amount of: (a) a CSF-1R inhibitor, (b) an IGF-1R inhibitor, and (c) a PI3K inhibitor.
3. The method of claim 1 , wherein the CSF-1R inhibitor is selected from the group consisting of BLZ945, GW2580, ABT-869 (linifanib), OSI-930, CEP-32496, AC708, PLX3397, AZD6495, CYC10268, IMC-CS4, RG7115, pyridyl bisamides, thiazolyl bisamides, 6-O-substituted benzoxazoles, and 6-O-substituted benzothiazoles.
4. The method of claim 1 , wherein the IGF-1R inhibitor is selected from the group consisting of OSI906 (linsitinib), NVP-AEW541, GSK1904529A, NVP-ADW742, BMS-536924, picropodophyllin (PPP), GSK1838705A, AG-1024, PQ401, and BMS-754807.
5. The method of claim 1 , wherein the PI3K inhibitor is selected from the group consisting of BKM120, idelaisib, SAR245409, SAR245408, BYL-719, GDC-0980, GDC-0941, wortmannin, Ly294002, demethoxyviridin, perifosine, delalisib, PX-866, IPI-145, BAY 80-6946, BEZ235, RP6530, TGR 1202, RP5264, SF1126, INK1117, Palomid 529, GSK1059615, ZSTK474, PWT33597, IC87114, TG100-115, CAL263, RP6503, PI-103, GNE-477, CUDC-907, and AEZS-136.
6. The method of claim 1 , wherein if either the CSF-1R inhibitor, the IGF-1R inhibitor, or the PI3K inhibitor is able to cross the blood brain barrier it is administered to the subject systemically, and if either the CSF-1R inhibitor, the IGF-1R inhibitor, or the PI3K inhibitor is not able to cross the blood brain barrier it is administered to the subject intracranially.
7. The method of claim 1 , wherein administration of the IGF-1R inhibitor and/or the PI3K inhibitor is commenced either (a) at approximately the same time as administration of the CSF-1R inhibitor is commenced, (b) after administration of the CSF-1R inhibitor is commenced, or (c) after the subject has developed resistance to CSF-1R inhibitor treatment.
8. The method of claim 1 , wherein the subject was previously treated with a CSF-1R inhibitor.
9. The method of claim 1 , wherein the glioma is a glioblastoma.
10. The method of claim 9 , wherein the glioblastoma is selected from the group consisting of proneural glioblastoma, Glioblastoma Multiforme (GBM), astrocytoma and oligodendroglioma.
11. The method of claim 1 , wherein the mammalian subject is selected from the group consisting of a rodent, a mouse, a non-human primate, and a human.
12. The method of claim 1 , wherein the mammalian subject is a human.
13. The method of claim 1 , wherein the subject is also treated by surgery, radiation therapy, chemotherapy, or anti-angiogenic therapy.
14. The method of claim 1 , wherein the CSF-1R inhibitor is BLZ945.
15. The method of claim 1 , wherein the IGF-1R inhibitor is OSI906.
16. The method of claim 1 , wherein the PI3K inhibitor is BKM120.
17. The method of claim 1 , comprising administering to the subject an effective amount of: (a) the CSF-1R inhibitor BLZ945, and (b) the IGF-1R inhibitor OSI906 or the PI3K inhibitor BKM120, thereby treating the CSF-1R inhibitor resistant glioma.
18. The method of claim 1 , comprising administering to the subject an effective amount of: (a) the CSF-1R inhibitor BLZ945, and (b) the IGF-1R inhibitor OSI906, thereby treating the CSF-1R inhibitor resistant glioma.
19. The method of claim 1 , comprising administering to the subject an effective amount of: (a) the CSF-1R inhibitor BLZ945, and (b) the PI3K inhibitor BKM120, thereby treating the CSF-1R inhibitor resistant glioma.