Methods of Treating Resistant Cancers

Patent metadata

Field	Value
Publication number	US-2020147047-A1
Application number	US-201816614147-A
Country	US
Kind code	A1
Filing date	May 18, 2018
Priority date	May 18, 2017
Publication date	May 14, 2020
Grant date	—

Abstract

Provided herein is a method for reducing resistance in an individual having a drug resistant cancer, for example, a BRAF inhibitor resistant cancer. A Hippo signaling pathway inhibitor such as a Yes-associated protein 1 (YAP1) inhibitor, a Transcriptional Coactivator with PDZ-binding motif (TAZ) inhibitor, a Transcription enhancer domain (TEAD) inhibitor or a combination of these is administered. Also provided is a method of treating BRAF inhibitor resistance in an individual with a BRAF inhibitor resistant cancer, for example, malignant melanoma, with a Hippo signaling pathway inhibitor, such as Verteporfin, and a BRAF inhibitor.

First claim

1 . A method of reducing resistance in an individual having a drug resistant cancer, comprising the step of:
administering to the individual a pharmacologically effective dose of a Hippo signaling pathway inhibitor.

2 . The method of claim 1 , wherein the Hippo signaling pathway inhibitor is a Yes-associated protein 1 (YAP1) inhibitor, a Transcriptional Coactivator with PDZ-binding motif (TAZ) inhibitor or a Transcription enhancer domain (TEAD) inhibitor or a combination thereof.

3 . The method of claim 2 , wherein the Hippo signaling pathway inhibitor is Verteporfin, Protoporphyrin IX, Zoledronic acid, Super-TDU, Auranofin, Metformin, Ivermectin and Milbemycin-D, Latrunculin A, Okadaic acid, Simvastatin, Staurosporine, Clomipramine, Heclin Dasatinib, Wortmannin, 4-((4-(3,4-Dichlorophenyl)-1,2,5-thiadiazol-3-yl)oxy)butane-1-ol 4-[2-[4-(4-Hydroxyphenyl)butan-2-ylamino]ethyl]benzene-1,2-diol (Dobutamine), 4-[(1 R)-1-Hydroxy-2-(methylamino)ethyl]benzene-1,2-diol (Epinephrine), 5-(2-phenylpyrazolo[1,5-a]pyridin-3-yl)-2H-pyrazolo[3,4-c]pyridazin-3-amine, 4-{[(1S)-1-Carboxy-3-methylbutyl]carbamoyl}-N-[(1H-imidazol-4-yl)methyl]-3-(naphthalen-1-yl)-anilinium trifluoroacetate, 2-[4-(Trifluoromethyl)phenyl]-1,5,7,8-tetrahydrothiopyrano[4,3-d]pyrimidin-4-one, 4-(1R)-1-aminoethyl]-N-pyridin-4-ylcyclohexane-1-carboxamide, Ac-KLRPVAMVRPVR-NH 2 (SEQ ID NO: 1), or Ac-GRKKRRQRRRPQKLRPαVAMVRPVR-NH 2 (SEQ ID NO: 2).

4 . The method of claim 3 , wherein the Hippo signaling pathway inhibitor is Verteporfin.

5 . The method of claim 1 , wherein said Hippo signaling pathway inhibitor is administered at a dosage of about 1 mg/kg to about 10 mg/kg.

6 . The method of claim 1 , wherein the drug resistant cancer is melanoma, colorectal cancer, cholangiocarcinoma, thyroid cancer, lung cancer, non-small-cell lung cancer, multiple myeloma, breast cancer, cervical cancer, ovarian cancer, gastric cancer, brain tumor, head and neck tumor, esophageal cancer, biliary tract cancer, pancreatic cancer, sarcoma, prostate cancer, or testicular cancer.

7 . The method of claim 1 , further comprising the step of:
administering to the individual a BRAF inhibitor.

8 . The method of claim 7 , wherein the BRAF inhibitor is vemurafenib, dabrafenib, encorafenib, methyl N-[6-[2-(5-chloro-2-methylphenyl)-1-hydroxy-3-oxoisoindol-1-yl]-1H-benzimidazol-2-yl] carbamate (BMS-908662), PLX3603, PLX4720 RAF265, or Sorafenib Tosylate.

9 . The method of claim 8 , wherein the BRAF inhibitor is vemurafenib, dabrafenib or encorafenib.

10 . The method of claim 7 , wherein the BRAF inhibitor is administered at a dosage of about 2 mg/kg to about 20 mg/kg.

11 . A method of reducing resistance in an individual with a BRAF inhibitor resistant cancer, comprising the step of:
administering to the individual a Hippo signaling pathway inhibitor.

12 . The method of claim 11 , wherein the BRAF inhibitor resistant cancer has a BRAFV600 mutation, a BRAFR461 mutation, a BRAFI462 mutation, a BRAFG463 mutation, a BRAFG463 mutation, a BRAFG465 mutation, a BRAFG465 mutation, a BRAFG468 mutation, a BRAFN580 mutation, a BRAFE585 mutation, a BRAFD593 mutation, a BRAFF594 mutation, a BRAFG595 mutation, a BRAFL596 mutation, a BRAFT598 mutation, a BRAFV599 mutation, or a BRAFA727 mutation or a combination thereof.

13 . The method of claim 12 , wherein the BRAFV600 mutation is a BRAFV600E mutation, a BRAFV600K mutation, a BRAFV600D mutation, or a BRAFV600R mutation.

14 . The method of claim 11 , wherein the BRAF inhibitor resistant cancer is melanoma, colorectal cancer, cholangiocarcinoma, thyroid cancer, lung cancer, non-small-cell lung cancer, multiple myeloma, breast cancer, cervical cancer, ovarian cancer, gastric cancer, brain tumor, head and neck tumor, esophageal cancer, biliary tract cancer, pancreatic cancer, sarcoma, prostate cancer, or testicular cancer.

15 . The method of claim 11 , wherein the Hippo signaling pathway inhibitor is a Yes-associated protein 1 (YAP1) inhibitor or a Transcriptional Coactivator with PDZ-binding motif (TAZ) inhibitor or a Transcription enhancer domain (TEAD) inhibitor or a combination thereof.

16 . The method of claim 15 , wherein the Hippo signaling pathway inhibitor is Verteporfin, Protoporphyrin IX, Zoledronic acid, Super-TDU, Auranofin, Metformin, Ivermectin and Milbemycin-D, Latrunculin A, Okadaic acid, Simvastatin, Staurosporine, Clomipramine, Heclin Dasatinib, Wortmannin, 4-((4-(3,4-Dichlorophenyl)-1,2,5-thiadiazol-3-yl)oxy)butane-1-ol, 4-[2-[4-(4-Hydroxyphenyl)butan-2-ylamino]ethyl]benzene-1,2-diol (Dobutamine), 4-[(1R)-1-Hydroxy-2-(methylam ino)ethyl]benzene-1,2-diol (Epinephrine), 5-(2-phenylpyrazolo[1,5-a]pyridin-3-yl)-2H-pyrazolo[3,4-c]pyridazin-3-amine, 4-{[(1S)-1-Carboxy-3-methylbutyl]carbamoyl}-N-[(1H-imidazol-4-yl)methyl]-3-(naphthalen-1-yl)-anilinium trifluoroacetate, 2-[4-(Trifluoromethyl)phenyl]-1,5,7,8-tetrahydrothiopyrano[4,3-d]pyrimidin-4-one, 4-[(1R)-1-aminoethyl]-N-pyridin-4-ylcyclohexane-1-carboxamide, Ac-KLRPVAMVRPVR-NH 2 (SEQ ID NO: 1), or Ac-GRKKRRQRRRPQKLRPVAMVRPVR-NH 2 (SEQ ID NO: 2).

17 . The method of claim 16 , wherein the Hippo signaling pathway inhibitor is Verteporfin.

18 . The method of claim 11 , further comprising the step of:
administering to the individual a BRAF inhibitor.

19 . The method of claim 18 , wherein the BRAF inhibitor is vemurafenib, dabrafenib, encorafenib, methyl N-[6-[2-(5-chloro-2-methylphenyl)-1-hydroxy-3-oxoisoindol-1-yl]-1H-benzim idazol-2-yl] carbamate (BMS-908662), PLX3603, PLX4720 RAF265, or Sorafenib Tosylate.

20 . The method of claim 19 , wherein the BRAF inhibitor is vemurafenib, dabrafenib or encorafenib.

21 . The method of claim 11 , wherein the BRAF inhibitor is administered at a dosage of about 2 mg/kg to about 20 mg/kg.

22 . A method of treating an individual having a BRAF inhibitor resistant cancer or at risk for developing BRAF inhibitor resistance, comprising the steps of:
administering to the individual a pharmacologically effective dose of Verteporfin and a pharmacologically effective dose of a BRAF inhibitor.

23 . The method of claim 22 , wherein the Verteporfin is administered at a pharmacologically effective dose of about 1 mg/kg to about 10 mg/kg.

24 . The method of claim 22 , wherein the BRAF inhibitor is vemurafenib, dabrafenib, encorafenib, methyl N-[6-[2-(5-chloro-2-methylphenyl)-1-hydroxy-3-oxoisoindol-1-yl]-1H-benzim idazol-2-yl] carbamate (BMS-908662), PLX3603, PLX4720 RAF265, or Sorafenib Tosylate.

25 . The method of claim 24 , wherein the BRAF inhibitor is vemurafenib, dabrafenib or encorafenib.

26 . The method of claim 22 , wherein the BRAF inhibitor is administered at a dosage of about 2 mg/kg to about 20 mg/kg.

27 . The method of claim 22 , wherein the BRAF inhibitor is administered before Verteporfin, after Verteporfin or with Verteporfin.

28 . The method of claim 22 , wherein the BRAF inhibitor resistant cancer has a BRAFV600 mutation, a BRAFR461 mutation, a BRAFI462 mutation, a BRAFG463 mutation, a BRAFG463 mutation, a BRAFG465 mutation, a BRAFG465 mutation, a BRAFG468 mutation, a BRAFN580 mutation, a BRAFE585 mutation, a BRAFD593 mutation, a BRAFF594 mutation, a BRAFG595 mutation, a BRAFL596 mutation, a BRAFT598 mutation, a BRAFV599 mutation, or a BRAFA727 mutation or a combination thereof.

29 . The method of claim 28 , wherein the BRAF inhibitor resistant c

Assignees

• Univ Maryland
• Univ Of Baltimore Maryland

Inventors

• Eckert Richard L
• Fisher Matthew
• Grun Daniel
• Adhikary Gautam
• Xu Wen

Classifications

• A61P35/00

  Antineoplastic agents · CPC title

• A61K31/506

  not condensed and containing further heterocyclic rings · CPC title

• A61K31/44

  Non condensed pyridines; Hydrogenated derivatives thereof · CPC title

• A61K31/437

  the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline · CPC title

• A61K31/409 Primary

  having four such rings, e.g. porphine derivatives, bilirubin, biliverdine (hemin, hematin A61K31/555) · CPC title