Methods for determining chemosensitivity and chemotoxicity

• US 10,640,803 B2
• Filed: 10/30/2014
• Issued: 05/05/2020
• 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.
• Primary Examiner(s): Lankford, Blaine
• Application Number:
  US15/033,810
• Publication Number:
  US 20160273020A1
• Time in Patent Office: 2,014 Days
• Field of Search: None
• 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. An in vitro method for treating a chronic lymphocytic leukemia (CLL) patient, comprising:

(a) determining in vitro a likelihood of an adverse response to one or more cancer treatments;

the determination comprising performing BH3 profiling of a cell specimen from the patient, wherein the BH3 profiling comprises;

(i) permeabilizing an aliquot of cells from the cell specimen from the patient;

(ii) contacting the aliquot of permeabilized cells with a BH3 domain peptide, wherein the BH3 domain peptide is at least one of BAD and PUMA peptides;

(iii) measuring the BH3 domain peptide-induced mitochondrial outer membrane permeabilization (MOMP) in the aliquot of cells to determine the BH3 profile, wherein;

the BH3 profile indicates an association between the at least one of BAD and PUMA peptides and the patient likelihood of the adverse response to the one or more cancer treatments, the association being established by performing Receiver Operator Characteristic (ROC)- plot analysis, wherein an area under the curve for the ROC plot analysis above 0.75 for the at least one of BAD and PUMA peptides indicates a high risk of the patient likelihood of the adverse response to the one or more cancer treatments;

wherein the one or more cancer treatments comprise treatment of the CLL patient with a cyclin-dependent kinase inhibitor;

(b) classifying the patient for likelihood of the adverse response to one or more cancer treatments, wherein the adverse response comprises tumor lysis syndrome (TLS), and

(c) administering the cyclin-dependent kinase inhibitor to a patient who is not classified as likely to have the TLS response.

2. The method of claim 1, 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.

3. The method of claim 1, 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.

4. The method of claim 1, further comprising determining one or more clinical factors of the patient.

5. The method of claim 4, 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.

6. The method of claim 4, wherein the clinical factor is one or more of age, cytogenetic risk status, performance, histological subclass, gender, Eastern Cooperative Oncology Group (ECOG) status, and disease stage.

7. The method of claim 4, wherein the clinical factor is one or more of ECOG status and patient age.

8. The method of claim 1, 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 classifying the patient for likelihood of a therapeutic efficacy to one or more cancer treatment.

9. The method of claim 8, wherein the BH3 profile for likelihood of a therapeutic efficacy to one or more cancer treatment comprises measuring levels of BIM and/or HRK.

10. The method of claim 8, wherein the therapeutic efficacy comprises a high clinical response and/or a high overall survival.

11. The method of claim 4, wherein the one or more clinical factors are selected to increase specificity and/or sensitivity of the BH3 profile for association with therapeutic efficacy.

12. The method of claim 4, wherein the clinical factor is trisomy 12 status.

13. The method of claim 1, further comprising measurement of an additional biomarker selected from mutational status, single nucleotide polymorphisms, steady state protein levels, and dynamic protein levels.

14. The method of claim 1, wherein the BH3 profiling is performed on purified B cells from the CLL patient.