Granted Patent
B2
US 12,324,807 · App. 15/733,852 · Granted Jun 10, 2025
Combination therapy for PI3K-associated disease or disorder
Inventors:
Lewis C. Cantley (Cambridge, MA); Benjamin Hopkins (Larchmont, NY); Marcus Goncalves (Garden City, NY); Siddhartha Mukherjee (New York, NY)
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Abstract
Described herein are compositions and methods for treating a disease or disorder associated with PI3K signaling. For example, such compositions can include use of modulators of glucose metabolism, use of at least one kinase in the insulin-receptor/PI3K/AKT/mTOR pathway, and/or use of diet that influences the subject's metabolic state.
Claims (40)
1. A method of improving the efficacy of a PI3K inhibitor in a treatment of a patient with a cancer that is pancreatic, breast, endometrial, bladder, leukemia, lung, or liver cancer the method comprising administering to the patient a PI3K inhibitor selected from copanlisib, buparlisib, alpelisib, taselisib, pictilisib or serabelisib in combination with a ketogenic diet that reduces serum insulin levels thereby improving the efficacy of the PI3K inhibitor wherein the ketogenic diet comprises at least 80% of fat and protein by weight.
2. The method of claim 1 , wherein the PI3K inhibitor is alpelisib, taselisib, or serabelisib.
3. The method of claim 1 , further comprising administering at least one modulator of glucose metabolism.
4. The method of claim 3 , wherein the at least one modulator of glucose metabolism is a sodium-glucose-linked transport protein 1 (SGLT1) inhibitor, a sodium-glucose-linked transport protein 2 (SGLT2) inhibitor, or a dual SGLT1/SGLT2 inhibitor.
5. The method of claim 3 , wherein the at least one modulator of glucose metabolism is dapagliflozin, empagliflozin, canagliflozin, ipragliflozin, tofogliflozin, sergliflozin etabonate, remogliflozin etabonate, ertugliflozin, or sotagliflozin.
6. The method of claim 3 , wherein the at least one modulator of glucose metabolism is a sodium-glucose-linked transport protein 2 (SGLT2) inhibitor.
7. The method of claim 3 , wherein the at least one modulator of glucose metabolism is metformin.
8. The method of claim 1 , wherein the patient is on the ketogenic diet before and during the administering of the copanlisib, buparlisib, alpelisib, taselisib, pictilisib or serabelisib.
9. The method of claim 1 , wherein the patient is on the ketogenic diet before the administering of the copanlisib, buparlisib, alpelisib, taselisib, pictilisib or serabelisib.
10. The method of claim 1 , wherein the patient is on the ketogenic diet during the administering of the copanlisib, buparlisib, alpelisib, taselisib, pictilisib or serabelisib.
11. The method of claim 1 , wherein the ketogenic diet comprises a 2.5:1 to a 3:1 ratio of grams of fat to grams of carbohydrate and protein combined.
12. The method of claim 1 , wherein the ketogenic diet comprises at most 10% of carbohydrate.
13. The method of claim 1 , wherein the ketogenic diet comprises about 90% of calories from fat and about 10% of calories from carbohydrate and protein combined.
14. The method of claim 1 , wherein the cancer is lung cancer.
15. The method of claim 1 , wherein the cancer is liver cancer.
16. The method of claim 1 , wherein the cancer is pancreatic cancer.
17. The method of claim 1 , wherein the cancer is endometrial cancer.
18. The method of claim 1 , wherein the cancer is bladder cancer.
19. The method of claim 1 , wherein the cancer is leukemia.
20. The method of claim 1 , wherein the cancer is breast cancer.
21. The method of claim 1 , wherein the cancer comprises one or more of a PIK3CA mutation and a PIK3R1 mutation.
22. The method of claim 1 , wherein the cancer comprises a PTEN alteration.
23. The method of claim 1 , wherein the cancer comprises a PTEN deletion.
24. The method of claim 1 , wherein the PI3K inhibitor inhibits one or more of p110-α, p110-β, p110-γ, p110-δ, p85-α, p85-β, p55-γ, p150, p101, p87, PI3K-C2α, PI3K-C2β, PI3K-C2γ, and Vps34.
25. The method of claim 1 , wherein the PI3K inhibitor is serabelisib.
26. The method of claim 25 , further comprising administering at least one modulator of glucose metabolism.
27. The method of claim 25 , wherein the cancer is endometrial cancer.
28. The method of claim 25 , wherein the cancer is breast cancer.
29. The method of claim 25 , wherein the method further comprises administering an mTOR inhibitor.
30. The method of claim 1 , wherein the method further comprises administering an mTOR inhibitor.
31. The method of claim 1 , wherein improving the efficacy of the PI3K inhibitor comprises reducing a level of PI3K signaling.
32. The method of claim 1 , wherein improving the efficacy of the PI3K inhibitor comprises one or more of reducing a level of phosphorylated AKT (pAKT) and reducing a level of phosphorylated S6 (pS6).
33. The method of claim 1 , wherein the method comprises measuring the serum insulin by ELISA or by a level of c-peptide.
34. The method of claim 1 , wherein the ketogenic diet reduces a marker of insulin signaling compared to treatment with the PI3K inhibitor without administration of the ketogenic diet.
35. The method of claim 34 , wherein the marker of insulin signaling is phosphorylated insulin receptor (pINSR).
36. The method of claim 1 , wherein the ketogenic diet reduces cell proliferation compared to treatment with the PI3K inhibitor without administration of the ketogenic diet.
37. The method of claim 36 , wherein the ketogenic diet reduces Ki67 levels or increases levels of apoptosis.
38. The method of claim 1 , wherein an effective amount of the PI3K inhibitor when in combination with the ketogenic diet is lower than an effective amount of the PI3K inhibitor without the ketogenic diet.
39. The method of claim 38 , wherein the effective amount of the PI3K inhibitor in combination with the ketogenic diet is less than about 90% of the effective amount of the PI3K inhibitor without the ketogenic diet.
40. The method of claim 1 , wherein the ketogenic diet comprises about 2% to about 5% of carbohydrates.
Assignments (2)
ASSIGNMENT OF ASSIGNOR'S INTEREST
Recorded Apr 21, 2021
From: MUKHERJEE, SIDDHARTHA
To: COLUMBIA UNIVERSITY
Reel/Frame 055988/0446 →
ASSIGNMENT OF ASSIGNOR'S INTEREST
Recorded Apr 21, 2021
From: CANTLEY, LEWIS C; HOPKINS, BENJAMIN; GONCALVES, MARCUS
To: CORNELL UNIVERSITY
Reel/Frame 055988/0564 →
Continuity (2)
Provisional Application
62679329
· Jun 1, 2018
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