Methods and compositions for identifying, classifying and monitoring subject having Bcl-2 family inhibitor-resistant tumors and cancers

• US 9,045,800 B2
• Filed: 02/11/2010
• Issued: 06/02/2015
• Est. Priority Date: 02/11/2009
• Status: Expired due to Fees

• Current Assignee: Abbvie Incorporated, The Walter & Eliza Hall Institute Of Medical Research
• Original Assignee: Abbvie Incorporated
• Inventors: Semizarov, Dimitri, Uziel, Tamar, Huang, David Ching Siang, van Delft, Mark F., Tse, Christin, Lesniewski, Richard R.
• Primary Examiner(s): MARSCHEL, ARDIN H
• Application Number:
  US12/704,165
• Publication Number:
  US 20100234239A1
• Time in Patent Office: 1,937 Days
• Field of Search: 435/6.1, 435/69.1
• US Class Current: 1/1
• 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 2600/156 Polymorphic or mutational markers
• CPC Class Codes: C12Q 2600/158 Expression markers
• CPC Class Codes: G01N 2333/4703 Regulators; Modulating activity
• CPC Class Codes: G01N 33/57496 involving intracellular compounds

Abstract

The invention is directed to methods and kits that allow for identifying, classifying, and monitoring cancer patients for Bcl-2 family inhibitor therapies. The methods and compositions of the invention are directed to determining amplification of Bcl-x_L and in cancer or tumor cells, or elevated Bcl-x_L polypeptide expression.

Claims

1. A method for identifying a patient with small-cell lung carcinoma or a lymphoma as eligible to receive N-(4-(4-((2-(4-chlorophenyl)-5,5-dimethyl-1-cyclohex-1-en-1-yl)methyl) piperazin-1-yl)benzoyl)-4-(((1R)-3-(morpholin-4-yl)-1-((phenylsulfanyl)methyl)propyl)amino)-3-((trifluoromethyl)sulfonyl)benzenesulfonamide therapy or an anti-sense agent designed to bind to one of Bcl-2, Bcl-w, and Bcl-x_L comprising:

(a) providing a tissue sample from a patient;

(b) determining if expression of a Bcl-x_L gene is amplified relative to a baseline control level determined before the administration of N-(4-(4-((2-(4-chlorophenyl)-5,5-dimethyl-1-cyclohex-1-en-1-yl)methyl)piperazin-1-yl)benzoyl)-4-(((1R)-3-(morpholin-4-yl)-1-((phenylsulfanyl)methyl)propyl)amino)-3-((trifluoromethyl)sulfonyl)benzenesulfonamide;

(c) identifying the patient as eligible to receive N-(4-(4-((2-(4-chlorophenyl)-5,5-dimethyl-1-cyclohex-1-en-1-yl)methyl)piperazin-1-yl)benzoyl)-4-(((1R)-3-(morpholin-4-yl)-1-((phenylsulfanyl)methyl)propyl)amino)-3-((trifluoromethyl)sulfonyl)benzenesulfonamide or the anti-sense agent designed to bind to one of Bcl-2, Bcl-w, and Bcl-x_L if the Bcl-x_L gene is not amplified; and

(d) administering N-(4-(4-((2-(4-chlorophenyl)-5,5-dimethyl-1-cyclohex-1-en-1-yl)methyl)piperazin-1-yl)benzoyl)-4-(((1R)-3-(morpholin-4-yl)-1-((phenylsulfanyl)methyl)propyl)amino)-3-((trifluoromethyl)sulfonyl)benzenesulfonamide or the anti-sense agent designed to bind to one of Bcl-2, Bcl-w, and Bcl-x_L to the patient identified as being eligible to receive N-(4-(4-((2-(4-chlorophenyl)-5,5-dimethyl-1-cyclohex-1-en-1-yl)methyl)piperazin-1-yl)benzoyl)-4-(((1R)-3-(morpholin-4-yl)-1-((phenylsulfanyl)methyl)propyl)amino)-3-((trifluoromethyl)sulfonyl)benzenesulfonamide or the anti-sense agent designed to bind to one of Bcl-2, Bcl-w, and Bcl-x_L.

2. The method of claim 1, wherein amplification of the Bcl-x_L gene correlates with an increase in expression of Bcl-x_L polypeptide.

3. The method of claim 1, wherein the tissue sample comprises a peripheral blood sample, a tumor tissue or a suspected tumor tissue, a thin layer cytological sample, a fine needle aspirate sample, a bone marrow sample, a lymph node sample, a urine sample, an ascites sample, a lavage sample, an esophageal brushing sample, a bladder or lung wash sample, a spinal fluid sample, a brain fluid sample, a ductal aspirate sample, a nipple discharge sample, a pleural effusion sample, a fresh frozen tissue sample, a paraffin embedded tissue sample or an extract or processed sample produced from any of a peripheral blood sample, a tumor tissue or a suspected tumor tissue, a thin layer cytological sample, a fine needle aspirate sample, a bone marrow sample, a urine sample, an ascites sample, a lavage sample, an esophageal brushing sample, a bladder or lung wash sample, a spinal fluid sample, a brain fluid sample, a ductal aspirate sample, a nipple discharge sample, a pleural effusion sample, a fresh frozen tissue sample or a paraffin embedded tissue sample.

4. The method of claim 1, wherein the determining step comprises in situ hybridization.

5. The method of claim 4, wherein the in situ hybridization is performed with a nucleic acid probe that is detectably labeled.

6. The method of claim 4, wherein the in situ hybridization is performed with a nucleic acid probe or peptide nucleic acid probe that specifically hybridizes to at least part of the Bcl-x_L gene.

7. The method of claim 1, wherein determining comprises a polymerase chain reaction.

8. The method of claim 7, wherein the polymerase chain reaction is performed with at least one primer that specifically hybridizes to at least part of a nucleic acid sequence of the Bcl-x_L gene.

9. The method of claim 1, wherein the determining step comprises a nucleic acid microarray assay.

10. A method for identifying a patient with small-cell lung carcinoma or a lymphoma as eligible to receive N-(4-(4-((2-(4-chlorophenyl)-5,5-dimethyl-1-cyclohex-1-en-1-yl)methyl)piperazin-1-yl)benzoyl)-4-(((1R)-3-(morpholin-4-yl)-1-((phenylsulfanyl)methyl)propyl)amino)-3-((trifluoromethyl)sulfonyl)benzenesulfonamide therapy or an anti-sense agent designed to bind to one of Bcl-2, Bcl-w, and Bcl-x_L comprising:

(a) providing a test sample from a patient;

(b) determining in the test sample;

(i) if a Bcl-x_L gene is amplified relative to a baseline control level determined before the administration of N-(4-(4-((2-(4-chlorophenyl)-5,5-dimethyl-1-cyclohex-1-en-1-yl)methyl)piperazin-1-yl)benzoyl)-4-(((1R)-3-(morpholin-4-yl)-1-((phenylsulfanyl)methyl)propyl)amino)-3-((trifluoromethyl)sulfonyl)benzenesulfonamide; and

(ii) an amount of Bcl-x_L in the test sample;

(c) determining if the amount of Bcl-x_L in the test sample is higher or lower than the amount of Bcl-x_L in a control, wherein the control is a level determined before the administration of N-(4-(4-((2-(4-chlorophenyl)-5,5-dimethyl-1-cyclohex-1-en-1-yl)methyl)piperazin-1-yl)benzoyl)-4-(((1R)-3-(morpholin-4-yl)-1-((phenylsulfanyl)methyl)propyl)amino)-3-((trifluoromethyl) sulfonyl)benzenesulfonamide; and

(d) identifying the patient as eligible to receive N-(4-(4-((2-(4-chlorophenyl)-5,5-dimethyl-1-cyclohex-1-en-1-yl)methyl)piperazin-1-yl)benzoyl)-4-(((1R)-3-(morpholin-4-yl)-1-((phenylsulfanyl)methyl)propyl)amino)-3-((trifluoromethyl)sulfonyl)benzenesulfonamide or the anti-sense agent designed to bind to one of Bcl-2, Bcl-w, and Bcl-x_L therapy based on;

(i) amplification of the Bcl-x_L gene; and

(ii) the amount of Bcl-x_L is higher in the test sample than in the control; and

(e) administering N-(4-(4-((2-(4-chlorophenyl)-5,5-dimethyl-1-cyclohex-1-en-1-yl)methyl)piperazin-1-yl)benzoyl)-4-(((1R)-3-(morpholin-4-yl)-1-((phenylsulfanyl)methyl)propyl)amino)-3-((trifluoromethyl)sulfonyl)benzenesulfonamide or the anti-sense agent designed to bind to one of Bcl-2, Bcl-w, and Bcl-x_L to the patient identified as being eligible to receive N-(4-(4-((2-(4-chlorophenyl)-5,5-dimethyl-1-cyclohex-1-en-1-yl)methyl)piperazin-1-yl)benzoyl)-4-(((1R)-3-(morpholin-4-yl)-1-((phenylsulfanyl)methyl)propyl)amino)-3-((trifluoromethyl)sulfonyl)benzenesulfonamide or the anti-sense agent designed to bind to one of Bcl-2, Bcl-w, and Bcl-x_L.

11. The method of claim 10, wherein the test sample comprises a peripheral blood sample, a tumor tissue or a suspected tumor tissue, a thin layer cytological sample, a fine needle aspirate sample, a bone marrow sample, a lymph node sample, a urine sample, an ascites sample, a lavage sample, an esophageal brushing sample, a bladder or lung wash sample, a spinal fluid sample, a brain fluid sample, a ductal aspirate sample, a nipple discharge sample, a pleural effusion sample, a fresh frozen tissue sample, a paraffin embedded tissue sample or an extract or processed sample produced from any of a peripheral blood sample, a tumor tissue or a suspected tumor tissue, a thin layer cytological sample, a fine needle aspirate sample, a bone marrow sample, a urine sample, an ascites sample, a lavage sample, an esophageal brushing sample, a bladder or lung wash sample, a spinal fluid sample, a brain fluid sample, a ductal aspirate sample, a nipple discharge sample, a pleural effusion sample, a fresh frozen tissue sample or a paraffin embedded tissue sample.

12. The method of claim 10, wherein determining amplification of the Bcl-x_L gene comprises in situ hybridization.

13. The method of claim 12, wherein the in situ hybridization is performed with a nucleic acid probe that is detectably labeled.

14. The method of claim 12, wherein the in situ hybridization is performed with a nucleic acid probe or peptide nucleic acid probe that specifically hybridizes to at least part of the Bcl-x_L gene.

15. The method of claim 10, wherein determining amplification of the Bcl-x_L gene comprises a polymerase chain reaction.

16. The method of claim 15, wherein the polymerase chain reaction is performed with at least one primer that specifically hybridizes to at least part of a nucleic acid sequence of the Bcl-x_L gene.

17. The method of claim 10, wherein the determining step comprises a nucleic acid microarray assay.

18. The method of claim 10, wherein the determining step (b)(ii) is performed by immunoassay.

19. The method of claim 18, wherein the immunoassay is a sandwich immunoassay.

20. The method of claim 18, wherein the immunoassay is an ELISA.

21. The method of claim 18, wherein the determining step (b)(ii) is performed on an automated immunoassay instrument.

22. The method of claim 10, wherein the determining step (b)(ii) is performed by measuring Bcl-x_L mRNA.