METHODS FOR DETERMINING DRUG EFFICACY FOR TREATMENT OF CANCER USING RATIOS OF CEREBLON ASSOCIATED PROTEINS

• US 20160356778A1
• Filed: 06/01/2016
• Published: 12/08/2016
• Est. Priority Date: 06/02/2015
• Status: Active Grant

• Current Assignee: Celgene Corporation (Bristol-Myers Squibb Company)
• Original Assignee: Celgene Corporation (Bristol-Myers Squibb Company), National University Corporation OITA University
• Inventors: IHA, Hidekatsu, IKEBE, Emi
• Granted Patent: US 10,338,077 B2
• Time in Patent Office: Days
• US Class Current: 1/1
• CPC Class Codes: A61K 31/454 containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 35/02 specific for leukemia
• CPC Class Codes: C12Q 1/6886 for cancer immunoassay for cancer G01N33/574
• CPC Class Codes: C12Q 2600/106 Pharmacogenomics, i.e. genetic variability in individual responses to drugs and drug metabolism
• CPC Class Codes: C12Q 2600/158 Expression markers
• CPC Class Codes: G01N 2333/47 Assays involving proteins of known structure or function as defined in the subgroups
• CPC Class Codes: G01N 2800/52 Predicting or monitoring the response to treatment, e.g. for selection of therapy based on assay results in personalised medicine; Prognosis
• CPC Class Codes: G01N 33/57426 leukemia
• CPC Class Codes: G01N 33/57484 involving compounds serving as markers for tumor, cancer, neoplasia, e.g. cellular determinants, receptors, heat shock/stress proteins, A-protein, oligosaccharides, metabolites

Abstract

A method of identifying a subject having cancer who is likely to be responsive to a treatment compound, comprising administering a treatment compound to a subject having cancer; obtaining a sample from the subject; determining the ratio of a first biomarker level to a second biomarker level in the sample from the subject, wherein at least one of the biomarkers is a CRBN-associated protein; and diagnosing the subject as being likely to be responsive to the treatment compound if the ratio of the biomarker levels in the sample of the subject changes as compared to a reference ratio of the biomarker levels.

Claims

1-3. -3. (canceled)

4. A method of identifying a subject having a cancer who is likely to be responsive to a treatment compound, predicting the responsiveness of a subject having or suspected of having a cancer to a treatment compound, or treating a cancer with a treatment compound in a subject, comprising:

(a) obtaining a sample from the subject;

(b) determining the ratio of a first biomarker level to a second biomarker level in the sample from the subject, wherein at least one of the biomarkers is a CRBN-associated protein;

(c) diagnosing the subject as being likely to be responsive to the treatment compound if the ratio of the biomarker levels in the sample of the subject is different from a reference ratio of the biomarker levels; and

(d) administering a therapeutically effective amount of the treatment compound to the subject diagnosed to be likely to be responsive to the treatment compound.

5. The method of claim 4, wherein in step (c) diagnosing the subject as being likely to be responsive to a treatment compound if the ratio of the biomarker levels in the sample of the subject is higher than a reference ratio of the biomarker levels.

6. The method of claim 4, wherein in step (c) diagnosing the subject as being likely to be responsive to a treatment compound if the ratio of the biomarker levels in the sample of the subject is lower than a reference ratio of the biomarker levels.

10. The method of claim 4, wherein the reference is prepared by using a control sample obtained from a subject having the cancer but not responsive to the compound treatment;

and wherein the control sample is from the same source as the sample.

11. The method of claim 4, wherein the reference is prepared by using a control sample obtained from a healthy subject not having the cancer;

and wherein the control sample is from the same source as the sample.

12. The method of claim 4, wherein the cancer is a leukemia.

13. The method of claim 4, wherein the cancer is a lymphoma.

14. The method of claim 12, wherein the cancer leukemia is an Adult T-cell Leukemia (ATL).

15. The method of claim 14, wherein the cancer is relapsed, refractory or resistant to conventional therapy.

16. The method of claim 14, wherein the treatment compound is an immunomodulatory compound.

17. The method of claim 16, wherein the treatment compound is lenalidomide.

19. The method of claim 4, wherein the first biomarker is selected from the group comprising CRBN, IKZF1, and IKZF2.

20. The method of claim 4, wherein the second biomarker is selected from the group comprising CRBN, IKZF1, and IKZF2.

21. The method of claim 4, wherein the first biomarker and the second biomarker are selected from the group comprising CRBN, IKZF1, and IKZF2, and wherein the ratio of the biomarker levels changes as compared to a reference.

22. The method of claim 21, wherein the ratio of the biomarker levels increases as compared to a reference.

23. The method of claim 21, wherein the ratio of the biomarker levels decreases as compared to a reference.

24. The method of claim 19, wherein the first biomarker is CRBN.

27. The method of claim 24, wherein the second biomarker is IKZF1.

28. The method of claim 27, wherein the ratio of the CRBN expression level to the IKZF1 expression level is higher than 3.

29. The method of claim 28, wherein the ratio of the CRBN expression level to the IKZF1 expression level is higher than 4.

30. The method of claim 29, wherein the ratio of the CRBN expression level to the IKZF1 expression level is higher than 5.

31. The method of claim 24, wherein the second biomarker is IKZF2.

32. The method of claim 31, wherein the ratio of the CRBN expression level to the IKZF2 expression level is between 500 and 5000.

33. The method of claim 32, wherein the ratio of the CRBN expression level to the IKZF2 expression level is higher than 500.

34. The method of claim 33, wherein the ratio of the CRBN expression level to the IKZF2 expression level is higher than 1000.

35. The method of claim 34, wherein the ratio of the CRBN expression level to the IKZF2 expression level is higher than 1500.

36. The method of claim 35, wherein the ratio of the CRBN expression level to the IKZF2 expression level is higher than 2500.

7. A method of monitoring the efficacy of a treatment of a cancer in a subject with a treatment compound, comprising:

(a) administering the treatment compound to the subject having the cancer;

(b) obtaining a sample from the subject;

(c) determining the ratio of a first biomarker level to a second biomarker level in the sample from the subject, wherein at least one of the biomarkers is a CRBN-associated protein; and

(d) comparing the ratio of the biomarker levels in the sample with the ratio of the biomarker levels obtained from a reference sample, wherein a change in the ratio as compared to the reference is indicative of the efficacy of the treatment compound in treating the cancer in the subject.

8. The method of claim 7, wherein an increased ratio as compared to the reference is indicative of the efficacy of the treatment compound in treating the cancer in the subject.

9. The method of claim 7, wherein a decreased ratio as compared to the reference is indicative of the efficacy of the treatment compound in treating the cancer in the subject.

18. (canceled)

25-26. -26. (canceled)

37-43. -43. (canceled)