Use of phosphoinositide 3-kinase inhibitors for treatment of vascular malformations

Patent metadata

Field	Value
Publication number	US-2018117055-A1
Application number	US-201715811973-A
Country	US
Kind code	A1
Filing date	Nov 14, 2017
Priority date	May 15, 2015
Publication date	May 3, 2018
Grant date	—

Abstract

The present disclosure relates to methods of treating a vascular malformation in a subject expressing a gain-of-function mutation in a PIK3CA gene comprising administering, to the subject, an effective amount of an agent that inhibits phosphoinositide 3-kinase (“PI3K”).

First claim

What is claimed is:

1 . A method of treating a vascular malformation in a subject, comprising administering, to the subject, an effective amount of an agent that inhibits the PI3K/AKT pathway.

2 . The method of claim 1 , wherein the subject has a gain-of-function mutation in the PI3K/AKT pathway.

3 . The method of claim 2 , wherein the gain-of-function mutation is an activating mutation of PIK3CA, or a mutation in one or more of AKTJ, AKT2, AKT3, and/or IRS2.

4 . The method of claim 3 , wherein the activation mutation is selected from the group consisting of R88Q, E542K, E545K, E545Q, H1047L, H1047Q, H1047R, C420R, and I143V.

5 . The method of claim 2 , wherein the agent that inhibits the PI3K/AKT pathway is an agent that selectively inhibits the alpha isoform (p110α) of PI3K.

6 . The method of claim 1 , wherein the agent that inhibits PI3K is selected from the group consisting of BYL719 (Alpelisib), BAY80-6946 (Copanlisib), CH5132799, GDC-0941 (Pictilisib), A66, PIK 90, and HS-173.

7 . The method of claim 1 , wherein the agent that inhibits the PI3K/AKT pathway is selected from the group consisting of GDC-0032, BKM-120, BEZ235, GNE-317, PI-103, PIK-75, BGT226, GSK1059615, PF-04691502, CNIO-PI3Ki, GSK2126558, XL147, PKI-402, GDC0980, BGT226, GSK1059615, PF-04691502, and MK2206.

8 . The method of claim 1 , wherein the vascular malformation is a) a venous malformation, b) in the brain, c) located within the skin, or d) a combination thereof.

9 . The method of claim 1 , wherein the subject
a) suffers from multiple vascular malformations, a malignancy, a multisystem genetic disorder or a combination thereof; b) suffers from at least one vascular malformation, the surgical treatment of which would be high-risk; or c) is not known to suffer from a malignancy or a multisystem genetic disorder.

10 . The method of claim 1 , wherein the agent that inhibits the PI3K/AKT pathway is administered systemically or locally.

11 . The method of claim 1 , wherein the agent that inhibits the PI3K/AKT pathway is administered topically, parenterally, or orally.

12 . A method of treating a vascular malformation in a subject, wherein the subject has a gain-of-function mutation in endothelial-specific tyrosine kinase receptor TEK (TIE2), comprising administering, to the subject, an effective amount of an agent that inhibits the PI3K/AKT pathway.

13 . A method of treating a vascular malformation in a subject comprising (i) determining whether the subject has a gain-of-function mutation in the PI3K/AKT pathway; and (ii) wherein the subject has a gain-of-function mutation in the PI3K/AKT pathway, treating the subject with an agent that inhibits the PI3K/AKT pathway, or, wherein the subject does not have an activating mutation of PIK3CA, treating with another modality such as surgery, embolization, or occlusion.

14 . The method of claim 13 , wherein the gain-of-function mutation in the PI3K/AKT pathway is an activating mutation in PIK3CA, or a mutation in one or more of AKT1, AKT2, AKT3, and/or IRS2.

15 . The method of claim 14 , wherein the activating mutation of PIK3CA is at amino acid 88, 542, 545, 1047, 420, or 143.

16 . The method of claim 15 , wherein the activation mutation is selected from the group consisting of R88Q, E542K, E545K, E545Q, H1047L, H1047Q, H1047R, C420R, and I143V.

17 . The method of claim 13 , wherein the agent that inhibits PI3K/AKT pathway is an agent that selectively acts at the alpha isoform (p110α) of PI3K.

18 . The method of claim 17 , wherein the agent that inhibits PI3K/AKT pathway is selected from the group consisting of BYLT19 (Alpelisib), BAY80-6946 (Copanlisib), CH5132799, GDC-0941 (Pictilisib), A66, PIK 90, and HS-173.

19 . The method of claim 13 , wherein the agent that inhibits the PI3K/AKT pathway is selected from the group consisting of GDC-0032, BKM-120, BEZ235, GNE-317, PI-103, PIK-75, BGT226, GSK1059615, PF-04691502, CNIO-PI3Ki, GSK2126558, XL147, PKI-402, GDC0980, BGT226, GSK1059615, PF-04691502, and MK2206.

20 . The method of claim 13 , wherein the vascular malformation is a venous malformation.

21 . The method of claim 13 , wherein the subject
a) suffers from multiple vascular malformations, a malignancy, a multisystem genetic disorder or a combination thereof; b) suffers from at least one vascular malformation, the surgical treatment of which would be high-risk; or c) is not known to suffer from a malignancy or a multisystem genetic disorder.

22 . The method of claim 13 , wherein the agent that inhibits the PI3K/AKT pathway is administered systemically or locally.

23 . The method of claim 13 , wherein the agent that inhibits the PI3K/AKT pathway is administered topically, parenterally, or orally.

24 . A method of treating a vascular malformation in a subject comprising (i) determining whether the subject has a gain-of-function mutation in endothelial-specific tyrosine kinase receptor TEK (TIE2); and (ii) wherein the subject has a gain-of-function mutation in TIE2, treating the subject with an agent that inhibits the PI3K/AKT pathway, or, wherein the subject does not have an activating mutation of PIK3CA, treating with another modality such as surgery, embolization, or occlusion.

25 . The method of claim 1 , further comprising treating the subject with a second agent that inhibits the PI3K/AKT pathway in an amount that, together with the agent of claim 1 , effectively treats the vascular malformation.

26 . A kit comprising a pharmaceutical formulation comprising an inhibitor of the PI3K/AKT pathway.

27 . A kit comprising a means of detecting a gain-in-function mutation of the PI3K/AKT pathway and instructions regarding treating a vascular malformation in a subject having such a mutation.

Assignees

• Memorial Sloan Kettering Cancer Center

Inventors

• Baselga Eulalia
• Castel Pau
• Baselga Jose T

Classifications

• A61K31/519 Primary

  ortho- or peri-condensed with heterocyclic rings · CPC title

• A61K31/427

  not condensed and containing further heterocyclic rings · CPC title

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title

• A61K31/444

  containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone · CPC title

• A61K31/4439

  containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole (nicotine A61K31/465) · CPC title