AKT and SHH Pathway Inhibitor Combination Therapy for Treating Basal Cell Carcinomas

• US 20170290849A1
• Filed: 09/08/2015
• Published: 10/12/2017
• Est. Priority Date: 09/05/2014
• Status: Abandoned Application

• Current Assignee: Trustees Of Columbia University In The City Of New York (Columbia University)
• Original Assignee: Trustees Of Columbia University In The City Of New York (Columbia University)
• Inventors: Kim, Arianna L., Bickers, David, Athar, Mohammad
• Application Number:
  US15/508,571
• Publication Number:
  US 20170290849A1
• Time in Patent Office: Days
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/4355 the heterocyclic ring system containing a five-membered ring having oxygen as a ring hetero atom
• CPC Class Codes: A61K 31/436 the heterocyclic ring system containing a six-membered ring having oxygen as a ring hetero atom, e.g. rapamycin
• CPC Class Codes: A61K 31/4375 the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine
• CPC Class Codes: A61K 31/4418 having a carbocyclic group directly attached to the heterocyclic ring, e.g. cyproheptadine
• CPC Class Codes: A61K 31/454 containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
• CPC Class Codes: A61K 31/496 Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
• CPC Class Codes: A61K 31/498 Pyrazines or piperazines ortho- and peri-condensed with carbocyclic ring systems, e.g. quinoxaline, phenazine
• CPC Class Codes: A61K 31/502 ortho- or peri-condensed with carbocyclic ring systems, e.g. cinnoline, phthalazine
• CPC Class Codes: A61K 31/506 not condensed and containing further heterocyclic rings
• CPC Class Codes: A61K 31/517 ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
• CPC Class Codes: A61K 31/519 ortho- or peri-condensed with heterocyclic rings
• CPC Class Codes: A61K 31/5377 not condensed and containing further heterocyclic rings, e.g. timolol
• CPC Class Codes: A61K 31/685 one of the hydroxy compounds having nitrogen atoms, e.g. phosphatidylserine, lecithin
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61K 9/0019 Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner non-active ingredients are additionally classified in A61K47/00
• CPC Class Codes: A61K 9/0053 Mouth and digestive tract, i.e. intraoral and peroral administration rectal administration A61K9/0031
• CPC Class Codes: A61P 35/00 Antineoplastic agents

Abstract

A mechanism whereby aberrant Shh signaling converges on the Akt1-mTOR pathway, conferring selective growth advantage and enhanced survival of tumor cells has been identified. Utilizing a mouse model of BCNS, a pivotal role has been discovered for Akt1 signaling in BCC tumorigenesis. Based on the results described here certain embodiments are directed to methods and pharmaceutical formulations for treating BCC/BCNS, other cancers that are Shh+ and Akt+, cancers that are Shh+ and mTOR plus and cancers that are Shh+ by administering therapeutically effective amounts of various combinations of Akt inhibitors, Shh pathway inhibitors such as SMO inhibitors, and mTOR inhibitors.

Claims

1. A method for treating basal cell carcinoma, basal cell nevus syndrome cancer, or XP BCC, comprising administering a therapeutically effective amount of an Akt inhibitor.

2. The method of claim 1, further comprising administering a therapeutically effective amount of an mTOR inhibitor or a sonic hedgehog pathway inhibitor.

3. The method of claim 1, further comprising administering a therapeutically effective amount of a sonic hedgehog pathway inhibitor and an mTOR inhibitor.

6. The method of claim 1, wherein the Akt inhibitor is selected from the group consisting of perifosine, edelfosine, MK-2206 and AZD5363 or pharmaceutically active derivatives thereof.

7. The method of claim 2, wherein the sonic hedgehog pathway inhibitor is a smoothened inhibitor.

8. The method of claim 7, wherein the smoothened inhibitor is a member selected from the group consisting of vismodegib and itraconazole, an agent listed in Table 1 or Table 2, or pharmaceutically active derivatives thereof.

9. The method of claim 2, wherein the mTOR inhibitor is selected from the group consisting of rapamycin Agent OSI-027, XL765, everolimius, temsirolimus and zotarolimus, or pharmaceutically active derivatives thereof.

19. The method of claim 1, wherein the dose is from about 0.1 mg/day to about 1 gm/day.

20. The method as of claim 1, wherein the of Akt inhibitor, is administered at a dose of about 1-25 mg/day, 25-50 mg/day, 50-100 mg/day, 100-200 mg/day, 200-300 mg/day, 400-500 mg/day and 500-1000 mg/day.

21. The method as of claim 2, wherein the sonic hedgehog pathway inhibitor is administered at a dose of about 1-25 mg/day, 25-50 mg/day, 50-100 mg/day, 100-200 mg/day, 200-300 mg/day, 400-500 mg/day and 500-1000 mg/day.

22. The method of claim 2, wherein the mTOR inhibitor is administered at a dose of about 1-25 mg/day, 25-50 mg/day, 50-100 mg/day, 100-200 mg/day, 200-300 mg/day, 400-500 mg/day and 500-1000 mg/day.

4. A method for treating a cancer that has activated sonic hedgehog and Akt, comprising administering a therapeutically effective amount of a sonic hedgehog pathway inhibitor and an Akt inhibitor, or a therapeutically effective amount of a sonic hedgehog pathway inhibitor and an mTOR inhibitor, a combination thereof.

10. The method of claim 4, wherein the sonic hedgehog- and Akt-activated cancer is a member from the group consisting of colon, pancreas, medulloblastoma, prostate, esophageal, glioma, and gastrointestinal cancers.

5. A method for treating a cancer that has activated sonic hedgehog and mTOR cancer, comprising administering a therapeutically effective amount of a sonic hedgehog pathway inhibitor and an mTOR inhibitor, or sonic hedgehog inhibitor, an Akt inhibitor and an mTOR inhibitor.

11. The method of claim 5, wherein the sonic hedgehog- and mTOR- activated cancer is a member from the group consisting of colon, pancreas, medulloblastoma, prostate, esophageal, glioma, and gastrointestinal cancers.

12. A pharmaceutical composition, comprising a therapeutically effective amount of an Akt1 inhibitor together with a sonic hedgehog pathway inhibitor or a therapeutically effective amount of an Akt1 inhibitor, sonic hedgehog pathway inhibitor and an mTOR inhibitor.

14. The pharmaceutical composition of claim 12, wherein the Akt inhibitor is selected from the group consisting of perifosine, edelfosine, MK-2206 and AZD5363 or pharmaceutically active derivatives thereof.

15. The pharmaceutical composition of claim 12, wherein the sonic hedgehog pathway inhibitor is a smoothened inhibitor.

16. The pharmaceutical composition of claim 15, wherein the smoothened inhibitor is a member selected from the group consisting of vismodegib and itraconazole, an agent listed in Table 1 or Table 2, or pharmaceutically active derivatives.

17. The pharmaceutical composition of claim 12, formulated for topical or oral administration.

18. The pharmaceutical composition of claim 12, formulated for administration by injection.

23. The pharmaceutical composition of claim 12, wherein the amount of sonic hedgehog inhibitor and the amount of Akt inhibitor respectively is from about 1-25 mg, 25-50 mg, 50-100 mg, 100-200 mg, 200-300 mg, 400-500 mg and 500-1000 mg.

13. (canceled)

24. The pharmaceutical composition of claim 13, wherein the amount of sonic hedgehog inhibitor, the amount of mTOR inhibitor and the amount of Akt inhibitor respectively is from about 1-25 mg, 25-50 mg, 50-100 mg, 100-200 mg, 200-300 mg, 400-500 mg and 500-1000 mg.