METHODS FOR DETERMINING CHEMOSENSITIVITY AND CHEMOTOXICITY

• US 20160273020A1
• Filed: 10/30/2014
• Published: 09/22/2016
• Est. Priority Date: 10/30/2013
• Status: Active Grant

• Current Assignee: Eutropics Pharmaceuticals, Inc.
• Original Assignee: Eutropics Pharmaceuticals, Inc.
• Inventors: PIERCEALL, William E., Cardone, Michael H.
• Granted Patent: US 10,640,803 B2
• Time in Patent Office: Days
• US Class Current: 1/1
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: C12Q 1/025 for testing or evaluating the effect of chemical or biological compounds, e.g. drugs, cosmetics antimicrobial activity C12Q1/18
• 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: G01N 2500/10 involving cells

Abstract

The present disclosure relates to diagnostic methods that are relevant to various cancers and which comprise BH3 profiling diagnostics for, among others, predication of an adverse patient response to a cancer treatment.

Claims

1. A method for determining an adverse response to one or more cancer treatments in a patient, comprising:

determining a BH3 profile for the patient'"'"'s cell specimen; and

classifying the patient for likelihood of an adverse response to one or more cancer treatments.

2. The method of claim 1, wherein the adverse response comprises tumor lysis syndrome (TLS).

3. The method of any of the above claims, wherein the BH3 profiling for determining the likelihood of an adverse response comprises measuring a response to BAD and/or PUMA.

4. The method of any of the above claims wherein a high likelihood of an adverse response to one or more cancer treatments directs treatment that comprises withholding of the one or more cancer treatments causing the adverse response.

5. The method of any of the above claims, wherein a high likelihood of an adverse response to one or more cancer treatments directs treatment that comprises administering one or more cancer treatments that do not comprise the one or more cancer treatments causing the adverse response.

6. The method of any of the above claims, further comprising determining one or more clinical factors of the patient.

7. The method of claim 6, wherein the one or more clinical factors are selected to increase specificity and/or sensitivity of the BH3 profile for association with an adverse response.

8. The method of claim 6 or 7, wherein the clinical factor is one or more of age, cytogenetic risk status, performance, histological subclass, gender, ECOG status, and disease stage

9. The method of claim 6-8, wherein the clinical factor is one or more of ECOG status and patient age.

10. The method of any of the above claims, wherein a low likelihood of an adverse response to one or more cancer treatments directs an evaluation of a therapeutic efficacy to the one or more cancer treatments;

wherein the evaluation comprises determining a BH3 profile for the patient'"'"'s tumor or cancer cell specimen and classifying the patient for likelihood of a therapeutic efficacy to one or more cancer treatment.

11. The method of claim 10, wherein the BH3 profile for likelihood of a therapeutic efficacy to one or more cancer treatment comprises measuring levels of BIM and/or HRK.

12. The method of claim 10 or 11, wherein the therapeutic efficacy comprises a high clinical response and/or a high overall survival.

13. The method of claims 9-12, further comprising determining one or more clinical factors of the patient.

14. The method of claim 13, wherein the one or more clinical factors are selected to increase specificity and/or sensitivity of the BH3 profile for association with therapeutic efficacy.

15. The method of claim 13 or 14, wherein the clinical factor is one or more of age, cytogenetic risk status, performance, histological subclass, gender, ECOG status, and disease stage.

16. The method of claims 13-15, wherein the clinical factor is trisomy 12 status.

17. The method of any of the above claims, farther comprising measurement of an additional biomarker selected from mutational status, single nucleotide polymorphisms, steady state protein levels, and dynamic protein levels.

18. The method of any of the above claims, wherein the BH3 profiling is performed on purified B cells from cancer patient.

19. The method of any of the above claims, wherein the cancer is a hematologic cancer.

20. The method of claim 19, wherein the hematologic cancer is selected from acute myelogenous leukemia (AML), multiple myeloma, follicular lymphoma, acute lymphoblastic leukemia (ALL), chronic lymphocytic leukemia, and non-Hodgkin'"'"'s lymphoma.

21. The method of claim 20, wherein the non-Hodgkin'"'"'s lymphoma is selected from mantle cell lymphoma and diffuse large B-cell lymphoma.

22. The method of any of the above claims, wherein the cancer is a solid tumor.

23. The method of claim 22, wherein the solid tumor is selected from non-small lung cell carcinoma, ovarian cancer, and melanoma.

24. The method of any of the above claims, wherein the cancer treatment is one or more of anti-cancer drugs, chemotherapy, surgery, adjuvant therapy, and neoadjuvant therapy.

25. The method of any of the above claims, wherein the cancer treatment is one or more of a BH3 mimetic, epigenetic modifying agent, topoisomerase inhibitor, cyclin-dependent kinase inhibitor, and kinesin-spindle protein stabilizing agent.

26. The method of any of the above claims, wherein the cancer treatment s a proteasome inhibitor.

27. The method of any of the above claims, wherein the cancer treatment is a modulator of cell cycle regulation.

28. The method of claim 27, wherein the modulator of cell cycle regulation is a cyclin dependent kinase inhibitor.

29. The method of any of the above claims, wherein the cancer treatment is a modulator of cellular epigenetic mechanistics.

30. The method of claim 29, wherein the modulator of epigenetics mechanistics is an inhibitor of histone deacetylase (HDAC) comprising one or more of vorinostat or entinostat.

31. The method of claim 29, wherein the modulator of epigenetics mechanistics is azacytidine.

32. The method of claim 29, wherein the modulator of epigenetics mechanistics is decitabine.

33. The method of any of the above claims, wherein the cancer treatment is an anthracycline or anthracenedione.

34. The method of claim 33, wherein the anthracycline or anthracenedione is one or more of epirubicin, doxonibicin, mitoxantrone, daunorubicin, idarubicin.

35. The method of any of the above claims, wherein the cancer treatment is a platinum-based therapeutic.

36. The method of claim 35, wherein the platinum-based therapeutic is one or more of carboplatin, cisplatin, and oxaliplatin.

37. The method of any of the above claims, wherein the cancer treatment is cytarabine or a cytarabine-based chemotherapy.

38. The method of any of the above claims, wherein the cancer treatment is a BH3 mimetic.

39. The method of claim 38, wherein the BH3 mimetic is one or more of BCL2, BCLXL, and MCL1.

40. The method of any of the above claims, wherein the cancer treatment is an inhibitor of MCL1.

41. The method of any of the above claims, wherein the BH3 profiling comprises permeabilizing the patient'"'"'s cancer cells, determining a change in mitochondrial membrane potential upon contacting the permeabilized cells with one or more BH3 domain peptides;

and correlating a loss of mitochondrial membrane potential with chemosensitivity of the cells to apoptosis-inducing chemotherapeutic agents.

42. The method of any of the above claims, wherein the BH3 profiling comprises a use of a peptide selected from one or more of BIM, BIM2A, BFL, BAD, BID, HRK, PUMA, NOXA, BMF, BIK, and PUMA2A.

43. The method of any of the above claims, wherein the BH3 profiling comprises a use of a peptide at a concentration of 0.1 μ

M to 200 μ

M.

44. The method of any of the above claims, wherein the specimen is a biopsy selected from a frozen tumor tissue specimen, cultured cells, circulating tumor cells, and a formalin-fixed paraffin-embedded tumor tissue specimen.

45. The method of claim 44, wherein the specimen is a human tumor-derived cell line.

46. The method of claim 44, wherein the specimen is a cancer stem cell.

47. The method of claim 44, wherein the specimen is derived from the biopsy of a solid tumor.

48. The method of claim 44, wherein the specimen is derived from the biopsy of a non-solid tumor.

49. The method of claim 44, wherein the specimen is derived from a circulating tumor cell.

55. The method of claim 1, wherein the adverse response is selected from the group consisting of thrombocytopenia, anemia, and an autoimmune reaction.

56. The method of any of the above claims, wherein the cell specimen comprises cells selected from the group consisting of platelets, erythroblast cells, immunomodulating cells, macrophages, dendritic cells, mast cells, and combinations thereof.

57. The method of any of the above claims, wherein a high likelihood of an adverse response to one or more cancer treatments directs treatment that comprises withholding of the one or more cancer treatments causing the adverse response.

50. A method for determining a treatment response to one or more cancer treatments in a blood cancer patient, comprising:

determining a BH3 profile for the patient'"'"'s tumor or cancer cell specimen; and

classifying the patient for likelihood of one or more of an adverse response to one or more cancer treatments and a therapeutic efficacy to one or more cancer treatments

wherein the a BH3 profile comprising BAD and/or PUMA responses is indicative of an adverse response to one or more cancer treatments and a BH3 profile comprising BIM and/or HRK responses is indicative of therapeutic efficacy to one or more cancer treatments.

51. The method of claim 50, wherein the blood cancer is CLL.

52. The method of claim 50, wherein the cancer treatment is a cyclin-dependent kinase inhibitor.

53. The method of claim 52, wherein the cyclin-dependent kinase inhibitor is alvocidib.

54. A method for determining an adverse response to one or more cancer treatments in a patient, comprising:

determining a BH3 profile for the patient'"'"'s cell population that is affected by the adverse event, and

classifying the patient for likelihood of an adverse response to one or more cancer treatments.