Methods of cancer treatment

• US 10,722,484 B2
• Filed: 03/09/2017
• Issued: 07/28/2020
• Est. Priority Date: 03/09/2016
• Status: Active Grant

• Current Assignee: K-Gen Therapeutics Incorporated
• Original Assignee: K-Gen, Inc.
• Inventors: Chen, Ruihong, Jiang, Chun
• Primary Examiner(s): Henley, III, Raymond J
• Application Number:
  US16/083,806
• Publication Number:
  US 20190298679A1
• Time in Patent Office: 1,237 Days
• Field of Search: 514546, 514547, 514549, 514550, 514551, 514557, 514561
• 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 31/122 having the oxygen directly attached to a ring, e.g. quinones, vitamin K1, anthralin
• CPC Class Codes: A61K 31/22 of acyclic acids, e.g. pravastatin
• CPC Class Codes: A61K 31/282 Platinum compounds
• CPC Class Codes: A61K 31/336 having three-membered rings, e.g. oxirane, fumagillin
• CPC Class Codes: A61K 31/337 having four-membered rings, e.g. taxol
• CPC Class Codes: A61K 31/365 Lactones
• 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 31/4402 only substituted in position 2, e.g. pheniramine, bisacodyl
• CPC Class Codes: A61K 31/502 ortho- or peri-condensed with carbocyclic ring systems, e.g. cinnoline, phthalazine
• CPC Class Codes: A61K 31/519 ortho- or peri-condensed with heterocyclic rings
• CPC Class Codes: A61K 31/52 Purines, e.g. adenine
• CPC Class Codes: A61K 31/551 having two nitrogen atoms, e.g. dilazep
• CPC Class Codes: A61K 33/243 Platinum; Compounds thereof
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61P 35/00 Antineoplastic agents

Abstract

This present disclosure is directed to a method of treating a subject with cancer with a combination of a protein kinase C (PKC) activator and a second therapeutic agent.

Claims

1. A method of treating cancer in a subject, comprising administering to a subject in need thereof a therapeutically effective amount of a diterpenoid protein kinase C (PKC) activator, and one or more of a therapeutic agent selected from phosphoinositol-3 kinase (PI3K) inhibitor, AKT inhibitor, mammalian target of rapamycin (mTOR) inhibitor, poly ADP ribose polymerase (PARP) inhibitor, CBP/β

-catenin inhibitor, Tankyrase (TNKS) inhibitor, probable protein-cysteine N-palmitoyltransferase (PORCN) inhibitor, scr kinase or bcr-abl kinase inhibitor, Smoothened (SMO) inhibitor, and combinations thereof, wherein the cancer is selected from the group consisting of the cancer of the pancreas, lung, colon, head and neck, stomach (gastric), biliary tract, endometrium, ovary, small intestine, urinary tract, liver, cervix, breast, kidney, renal, and hematologic cancers.

6. The method of claim 1, wherein the cancer is identified as having an activating or oncogenic K-RAS, N-RAS, or H-RAS activity.

7. The method of claim 1, further comprising measuring the protein kinase C activation potential by assessing the phosphorylation level of one or more of PKC α

, β

, γ

, δ

, ε

, η

, θ

, t/λ

, μ and

ζ

proteins.

8. The method of claim 7, wherein the phosphorylation level is determined following contacting the cancer with the diterpenoid PKC activator.

10. The method of claim 1, wherein the diterpenoid PKC activator is a PKC activating phorbol, deoxyphorbol, ingenol, daphnane, or lathyrane compound, or derivatives, analogs, or prodrugs thereof.

11. The method of claim 10, wherein the PKC activator is a compound of structural formula (PI):

12. The method of claim 11, wherein the PKC activator is a compound of structural formula (PIT):

13. The method of claim 11, wherein, the PKC activator is compound of structural formula (PIII):

14. The method of claim 13, wherein the PKC activator comprises a compound of formula (PIIIc):

15. The method of claim 11, wherein the PKC activator comprises a compound of formula (PIV):

16. The method of claim 15, wherein the PKC activator comprises a compound of formula (PIVc):

24. The method of claim 1, wherein the one or more therapeutic agent is selected from poly ADP ribose polymerase (PARP) inhibitor, scr kinase or bcr-abl kinase inhibitor, Smoothened (SMO) inhibitor, and combinations thereof.

2. A method of treating cancer, comprising administering to a subject in need thereof a therapeutically effective amount of a diterpenoid protein kinase C (PKC) activator, and one or more of an inhibitor of PI3K/AKT/mTOR signaling pathway, wherein the cancer is selected from the group consisting of the cancer of the pancreas, lung, colon, head and neck, stomach (gastric), biliary tract, endometrium, ovary, small intestine, urinary tract, liver, cervix, breast, kidney, renal, and hematologic cancers.

3. The method of claim 2, wherein the one or more of an inhibitor of PI3K/AKT/mTOR signaling pathway is selected from a PI3K inhibitor, AKT inhibitor, mTOR inhibitor, and combinations thereof.

4. A method of treating cancer in a subject, comprising administering to a subject in need thereof a therapeutically effective amount of a diterpenoid protein kinase C activator, and one or more of an inhibitor of Wnt/β

-catenin signaling pathway, wherein the cancer is selected from the group consisting of the cancer of the pancreas, lung, colon, head and neck, stomach (gastric), biliary tract, endometrium, ovary, small intestine, urinary tract, liver, cervix, breast, kidney, renal, and hematologic cancers.

5. The method of claim 4, wherein the one or more of an inhibitor of Wnt/β

-catenin signaling pathway is selected from CBP/β

-catenin inhibitor, TNKS inhibitor, PORCN inhibitor, and combinations thereof.

9. A method of treating a leukemia or lymphoma in a subject, comprising administering to a subject in need thereof a therapeutically effective amount of a diterpenoid PKC activator, and a therapeutic agent selected from a PI3K inhibitor, scr kinase or bcr-abl kinase inhibitor, histone deacetylase (HDAC) inhibitor, Bromodomain and Extra-Terminal motif (BET) inhibitor, all-trans-retinoic acid (ATRA), Bruton'"'"'s tyrosine kinase (BTK) inhibitor, anti-cancer nucleoside analog, and combinations thereof.

17. The method of claim 9, wherein the diterpenoid PKC activator is a PKC activating phorbol, deoxyphorbol, ingenol, daphnane, or lathyrane compound, or derivatives, analogs, or prodrugs thereof.

18. The method of claim 17, wherein the PKC activator is a compound of structural formula (PI):

19. The method of claim 18, wherein the PKC activator is a compound of structural formula (PII):

20. The method of claim 18, wherein, the PKC activator is compound of structural formula (PIII):

21. The method of claim 20, wherein the PKC activator comprises a compound of formula (PIIIc):

22. The method of claim 18, wherein the PKC activator comprises a compound of formula (PIV):

23. The method of claim 22, wherein the PKC activator comprises a compound of formula (PIVc):

25. The method of claim 9, wherein the therapeutic agent is selected from histone deacetylase (HDAC) inhibitor, Bromodomain and Extra-Terminal motif (BET) inhibitor, and combinations thereof.

26. The method of claim 9, wherein the therapeutic agent is selected from all-trans-retinoic acid (ATRA), Bruton'"'"'s tyrosine kinase (BTK) inhibitor, and combinations thereof.

27. The method of claim 9, wherein the therapeutic agent is selected from a PI3K inhibitor, scr kinase or bcr-abl kinase inhibitor, and combinations thereof.