Combination therapy using pdk1 and pi3k inhibitors

Patent metadata

Field	Value
Publication number	US-2018147232-A1
Application number	US-201815873324-A
Country	US
Kind code	A1
Filing date	Jan 17, 2018
Priority date	Jul 17, 2015
Publication date	May 31, 2018
Grant date	—

Abstract

The present invention relates to methods and compositions for inhibiting growth and proliferation of cancer cells resistant to PI3K inhibition using a combination of PDK1, SGK1 and PI3K inhibitors. The present invention is also directed to methods of treating cancer in a subject exhibiting cancer cells resistant to PI3K inhibition, comprising administering inhibitors of PI3K in combination with inhibitors of PDK1 and/or SGK1 to the subject.

First claim

What is claimed is:

1 . A method of treating cancer in a subject comprising administering, to a subject in need thereof, an effective amount of an agent that inhibits the PI3K/AKT pathway and an effective amount of an agent that inhibits PDK1 activity, the SGK1 pathway, or a combination thereof.

2 . The method of claim 1 , wherein the cancer comprises cells that are resistant to PI3K/ATK inhibitor monotherapy.

3 . The method of claim 1 , wherein the method comprises administering an effective amount of an agent that inhibits the PI3K/AKT pathway and an effective amount of an agent that inhibits PDK1 activity.

4 . The method of claim 1 , wherein the method comprises administering an effective amount of an agent that inhibits the PI3K/AKT pathway and an effective amount of an agent that inhibits the SGK1 pathway.

5 . The method of claim 1 , 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 5 , wherein the agent comprises a nucleic acid that specifically binds to a nucleic acid encoding p110α, and reduces PI3K activity and/or expression.

7 . The method of claim 6 , wherein the agent comprises a micro RNA (miRNA) molecule, interfering RNA (RNAi) molecule, shRNA molecule, antisense RNA molecule, catalytic RNA molecule, and/or catalytic DNA molecule.

8 . The method of claim 5 , wherein the agent that inhibits PI3K is selected from the group consisting of BYL719 (Apelisib), BAY80-6946 (Copanlisib), CH5132799, GDC-0941 (Pictilisib), A66, PIK 90, HS-173, MLN1117, GDC-0032, and combinations thereof.

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

10 . The method of claim 3 , wherein the agent that inhibits PDK1 activity comprises a nucleic acid that specifically binds to a nucleic acid encoding PDK1, and reduces PDK1 activity and/or expression.

11 . The method of claim 10 , wherein the agent comprises a micro RNA (miRNA) molecule, interfering RNA (RNAi) molecule, shRNA molecule, antisense RNA molecule, catalytic RNA molecule, and/or catalytic DNA molecule.

12 . The method of claim 3 , wherein the agent that inhibits PDK1 activity is selected from the group consisting of GSK2334470, BX-912, BX-795, BAG 956, OSU 03012, PHT-427, and combinations thereof.

13 . The method of claim 4 , wherein the agent that inhibits the SGK1 pathway comprises a nucleic acid that specifically binds to a nucleic acid encoding SGK1, and reduces SGK1 activity and/or expression.

14 . The method of claim 13 , wherein the agent comprises a micro RNA (miRNA) molecule, interfering RNA (RNAi) molecule, shRNA molecule, antisense RNA molecule, catalytic RNA molecule, and/or catalytic DNA molecule.

15 . The method of claim 4 , wherein the agent is selected from the group consisting of GSK650394, SI113, and combinations thereof.

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

17 . The method of claim 16 , wherein the gain-of-function mutation in the PI3K/AKT pathway is an activating mutation in PIK3CA.

18 . The method of claim 17 , wherein the gain-of-function mutation in the PI3K/AKT pathway comprises a mutation at amino acid 88, 143, 345, 420, 542, 545, and/or 1047 of the PIK3CA amino acid sequence.

19 . The method of claim 18 , wherein the mutation in PIK3CA is selected from the group consisting of R88Q, N345K, E542K, E545K, E545Q, H1047L, H1047Q, H1047R, C420R, I143V, and combinations thereof.

20 . The method of claim 1 , wherein the cancer is breast cancer.

21 . A method of treating cancer in a subject comprising:
(i) determining whether the subject expresses cancer cells that are resistant to treatment with a PI3K/AKT pathway inhibitor, wherein the resistant cells treated with the inhibitor sustain mTORC1 activity; and (ii) where the subject expresses cancer cells that are resistant to treatment with a PI3K/AKT pathway inhibitor, treating the subject with an agent that inhibits the PI3K/AKT pathway and an agent that inhibits PDK1 activity, a SGK1 pathway, or a combination thereof.

22 . A kit comprising one or more agent that can (i) decrease the activity of mTORC1; (ii) decrease the activity PI3K and decrease the activity of PDK1 and/or SGK1; and (iii) reduce or inhibit cancer cell and/or tumor cell growth

23 . A kit comprising an agent that inhibits the PI3K/AKT pathway and an agent that inhibits PDK1 activity, SGK1 pathway, or a combination thereof.

24 . A pharmaceutical composition for use in treating cancer in a subject in need thereof, comprising an effective amount of an agent that inhibits the PI3K/AKT pathway and an effective amount of an agent that inhibits PDK1 activity, the SGK1 pathway, or a combination thereof.

Assignees

• Memorial Sloan Kettering Cancer Center

Inventors

• Castel Pau
• Baselga Jose T
• Scaltriti Maurizio

Classifications

• A61K31/506

  not condensed and containing further heterocyclic rings · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61K31/4439

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

• A61K31/713 Primary

  Double-stranded nucleic acids or oligonucleotides · CPC title

• A61K31/7105

  Natural ribonucleic acids, i.e. containing only riboses attached to adenine, guanine, cytosine or uracil and having 3'-5' phosphodiester links · CPC title