Biomarkers of response to NAE inhibitors

Patent metadata

Field	Value
Publication number	US-9827246-B2
Application number	US-201214354149-A
Country	US
Kind code	B2
Filing date	Oct 26, 2012
Priority date	Oct 28, 2011
Publication date	Nov 28, 2017
Grant date	Nov 28, 2017

Abstract

Disclosed herein are markers whose mutational status is associated with sensitivity to treatment with NAE inhibitors. Mutational status is determined by measurement of characteristics of markers associated with the marker genes. Compositions and methods are provided to assess markers of marker genes to predict response to NAE inhibition treatment.

First claim

What is claimed:

1. A method of treating cancer comprising:
a) identifying a cancer patient having a mutation in at least one human marker gene selected from the group consisting of human neurofibromin 2 (NF2), human mothers against decapentaplegic homolog 4 (SMAD4), human lysine-specific demethylase 6A (KDM6A), and human F-box and WD repeat domain containing 7 (FBXW7); and
b) administering a NEDD8-activating enzyme (NAE) inhibitor to the cancer patient, wherein the NAE inhibitor comprises ((1 S,2S,4R)-4-{4-[(1S)-2,3-dihydro-1H-inden-1-ylamino]-7H-pyrrolo[2,3-d]pyrimidin-7-yl}-2-hydroxycyclopentyl)methyl sulphamate or a pharmaceutically acceptable salt thereof.

2. The method of claim 1 , wherein the mutation is an inactivating mutation.

3. The method of claim 1 , wherein identifying a cancer patient having a mutation in at least one human marker gene selected from the group consisting of NF2, SMAD4, KDM6A, and FBXW7 comprises:
a) obtaining a tumor sample from the cancer patient: and
b) detecting a mutation in an NF2, SMAD4, KDM6A, or FBXW7 protein, or a nucleic acid encoding that protein, relative to a wild-type human protein or nucleic acid.

4. The method of claim 3 , wherein the nucleic acid is selected from the group consisting of DNA, mRNA and cDNA or a region of any of the foregoing, wherein the region corresponds to at least one mutation site of the at least one marker gene.

5. The method of claim 3 , further comprising adding a nucleic acid probe that binds to the NF2, SMAD4, KIDM6A, or FBXW7 nucleic acid if the nucleic acid has a mutation.

6. The method of claim 3 , further comprising adding an antibody that binds to the NF2, SMAD4, KDM6A, or FBXW7 protein if the protein has a mutation.

7. The method of claim 3 , wherein the tumor sample comprises hematological tumor cells or solid tumor cells.

8. The method of claim 7 , wherein the tumor sample comprising hematological tumor cells is a bone marrow biopsy or blood.

9. The method of claim 8 , further comprising enriching the hematological tumor cells in the tumor sample.

10. The method of claim 3 , further comprising sequencing the nucleic acid, sequencing the protein, or identifying the mutation in the protein by mass spectrometry.

11. The method of claim 1 , wherein the cancer is a hematological cancer or a solid tumor cancer.

12. The method of claim 11 , wherein the hematological cancer is acute myelogenous leukemia.

13. The method of claim 11 , wherein the solid tumor cancer is head and neck cancer.

14. The method of claim 1 , further comprising:
a) obtaining a tumor sample from the cancer patient after administering the NAE inhibitor;
b) detecting a mutation in at least one human marker gene in the tumor sample, wherein the at least one human marker gene is selected from the group consisting of human NF2, SMAD4, KDM6A and FBXW7; and
b) continuing to administer the NAE inhibitor to the cancer patient.

15. The method of claim 1 , wherein the hematological cancer is myelodysplastic syndrome.

16. The method of claim 1 , wherein the at least one human marker gene is NF2.

17. The method of claim 1 , wherein the at least one human marker gene is SMAD4.

18. The method of claim 1 , wherein the at least one human marker gene is KDM6A.

19. The method of claim 1 , wherein the at least one human marker gene is FBXW7.

20. The method of claim 1 , wherein the pharmaceutically acceptable salt is a hydrochloride salt.

21. A method of treating cancer, comprising administering an NAE inhibitor to a subject having a mutation in at least one human marker gene selected from the group consisting of human NF2, SMAD4, KDM6A, and FBXW7, wherein the NAE inhibitor comprises ((1S,2S,4R)-4-{4-[(1S)-2,3-dihydro-1H-inden-1-ylamino]-7H-pyrrolo[2,3-d]pyrimidin-7-yl}-2-hydroxycyclopentyl)methyl sulphamate or a pharmaceutically acceptable salt thereof.

22. The method of claim 21 , wherein the pharmaceutically acceptable salt is a hydrochloride salt.

23. The method of claim 21 , wherein the cancer is a hematological cancer or a solid tumor cancer.

24. The method of claim 23 , wherein the hematological cancer is acute myelogenous leukemia.

25. The method of claim 23 , wherein the hematological cancer is myelodysplastic syndrome.

26. The method of claim 23 , wherein the solid tumor cancer is head and neck cancer.

27. The method of claim 21 , further comprising obtaining a tumor sample obtained from the subject and identifying a mutation.

28. The method of claim 27 , wherein the tumor sample comprises hematological tumor cells or solid tumor cells.

29. The method of claim 28 , wherein the tumor sample comprising hematological tumor cells is a bone marrow biopsy or blood.

30. The method of claim 21 , wherein the at least one human marker gene is NF2.

31. The method of claim 21 , wherein the at least one human marker gene is SMAD4.

32. The method of claim 21 , wherein the at least one human marker gene is KDM6A.

33. The method of claim 21 , wherein the at least one human marker gene is FBXW7.

Assignees

• Millennium Pharm Inc

Inventors

• Blakemore Stephen J
• Li Bin
• Mulligan George J
• Schu Matthew C
• Smith Peter G

Classifications

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61P35/02

  specific for leukemia · CPC title

• G01N33/5758

  involving compounds serving as markers for tumours, cancers or neoplasias, e.g. cellular determinants, receptors, heat shock/stress proteins, A-protein, oligosaccharides or metabolites · CPC title

• C12Q2600/106

  Pharmacogenomics, i.e. genetic variability in individual responses to drugs and drug metabolism · CPC title