Molecular diagnostic test for cancer

• US 10,378,066 B2
• Filed: 02/07/2017
• Issued: 08/13/2019
• Est. Priority Date: 09/15/2010
• Status: Active Grant

• Current Assignee: Almac Diagnostic Services Limited
• Original Assignee: Almac Diagnostic Services Limited
• Inventors: O'Donnell, Jude, Bylesjo, Max, Patterson, Fionnuala, Deharo, Steve, Hill, Laura A., Keating, Katherine E., Davison, Timothy, Proutski, Vitali, Harkin, Denis Paul, Kennedy, Richard, Goffard, Nicolas
• Primary Examiner(s): Zhang, Kaijiang
• Application Number:
  US15/426,923
• Publication Number:
  US 20170198360A1
• Time in Patent Office: 917 Days
• Field of Search: None
• CPC Class Codes: A61K 33/243 Platinum; Compounds thereof
• CPC Class Codes: C12Q 1/6876 Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes
• 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 2600/112 Disease subtyping, staging or classification
• CPC Class Codes: C12Q 2600/158 Expression markers
• CPC Class Codes: C40B 30/04 by measuring the ability to specifically bind a target molecule, e.g. antibody-antigen binding, receptor-ligand binding
• CPC Class Codes: G16B 25/00 ICT specially adapted for hybridisation; ICT specially adapted for gene or protein expression
• CPC Class Codes: G16B 25/10 Gene or protein expression profiling; Expression-ratio estimation or normalisation
• CPC Class Codes: G16B 40/00 ICT specially adapted for biostatistics; ICT specially adapted for bioinformatics-related machine learning or data mining, e.g. knowledge discovery or pattern finding
• CPC Class Codes: G16B 40/20 Supervised data analysis
• CPC Class Codes: G16H 50/30 for calculating health indices; for individual health risk assessment

Abstract

Methods and compositions are provided for the identification of a molecular diagnostic test for cancer. The test defines a novel DNA damage repair deficient molecular subtype and enables classification of a patient within this subtype. The present invention can be used to determine whether patients with cancer are clinically responsive or non-responsive to a therapeutic regimen prior to administration of any chemotherapy. This test may be used in different cancer types and with different drugs that directly or indirectly affect DNA damage or repair, such as many of the standard cytotoxic chemotherapeutic drugs currently in use. In particular, the present invention is directed to the use of certain combinations of predictive markers, wherein the expression of the predictive markers correlates with responsiveness or non-responsiveness to a therapeutic regimen.

Claims

1. A method of predicting response of an individual to, and treating an individual with, a modulator of DNA-damage-related immune signalling, comprising:

a. measuring expression levels of at least five biomarkers in a test sample of cancer cells obtained from the individual, wherein the at least five biomarkers are selected from the group consisting of CXCL10, MX1, IDO1, IFI44L, CD2, GBP5, PRAME, ITGAL, LRP4, and APOL3;

b. deriving a combined test score that captures the expression levels;

c. providing a threshold score comprising information correlating the test score and responsiveness to the modulator of DNA-damage-related immune signalling;

wherein the individual is predicted to respond to the modulator of DNA-damage-related immune signalling when the test score exceeds the threshold score; and

d. treating the individual that is so predicted to respond with the modulator of DNA-damage-related immune signalling.

2. The method of claim 1, further comprising measuring expression level(s) of one or more additional biomarkers in the test sample wherein the one or more additional biomarkers are selected from the group consisting of CDR1, FYB, TSPAN7, RAC2, KLHDC7B, GRB14, AC138128.1, KIF26A, CD274, CD109, ETV7, MFAP5, OLFM4, PI15, FOSB, FAM19A5, NLRC5, PRICKLE1, EGR1, CLDN10, ADAMTS4, SP140L, ANXA1, RSAD2, ESR1, IKZF3, OR2I1P, EGFR, NAT1, LATS2, CYP2B6, PTPRC, PPP1R1A, and AL137218.1.

3. The method of claim 1, wherein the test score captures the expression levels of all biomarkers from the group consisting of CXCL10, MX1, IDO1, IFI44L, CD2, GBP5, PRAME, ITGAL, LRP4, and APOL3, and wherein the individual is diagnosed as having a DDRD cancer when the test score exceeds the threshold score.

4. The method of claim 1, wherein the cancer is selected from melanoma, breast cancer, and ovarian cancer.

5. The method of claim 4, wherein the cancer is associated with one or more mutations in the Fanconi anemia/BRCA pathway.

6. The method of claim 1, wherein the modulator of DNA-damage-related immune signalling is selected from cisplatin and ionising radiation.

7. The method of claim 1, wherein at least one of the biomarkers is CXCL10.

8. A method of predicting response of an individual to, and treating an individual with, a DNA-damage therapeutic agent, comprising:

a. measuring expression levels of at least five biomarkers in a test sample of cancer cells obtained from the individual, wherein the at least five biomarkers are selected from the biomarkers in Table 2B;

b. deriving a combined test score that captures the expression levels;

c. providing a threshold score comprising information correlating the test score and responsiveness to a DNA-damage therapeutic agent;

wherein the individual is predicted to respond to a DNA-damage therapeutic agent when the test score exceeds the threshold score; and

d. treating the individual that is so predicted to respond with a DNA-damage therapeutic agent.

9. The method of claim 8, wherein the combined test score captures the expression levels of all 44 biomarkers in Table 2B, and wherein the individual is diagnosed as having a DDRD cancer when the test score exceeds a threshold score calculated using the weights of Table 2B.

10. The method of claim 8, wherein the cancer is selected from melanoma, breast cancer, and ovarian cancer.

11. The method of claim 10, wherein the cancer is associated with one or more mutations in the Fanconi anemia/BRCA pathway.

12. The method of claim 8, wherein the DNA-damage therapeutic agent comprises one or more substances selected from the group consisting of:

a DNA damaging agent, a DNA repair targeted therapy, an inhibitor of DNA damage signalling, an inhibitor of DNA damage induced cell cycle arrest, a histone deacetylase inhibitor, and a heat shock protein inhibitor.

13. The method of claim 8, wherein the DNA-damage therapeutic agent is a modulator of DNA-damage-related immune signalling.

14. The method of claim 12, wherein the DNA damaging agent is selected from cisplatin, carboplatin, oxaliplatin and cyclophosamide;

the Topoisomerase I inhibitors Irinotecan and toptecan;

the Topoisomerase II inhibitors etoposide, doxorubicin, and epirubicin;

ionising radiation;

the DNA repair targeted DNA-PK inhibitors Nu7441 and NU7026, PARP inhibitors, AZD2281, AG014699, ABT-888, MK4827, BSI-201, and TRC-102;

the inhibitors of DNA damage signalling ATM inhibitors CP466722 and KU-55933;

the CHK1/CHK2 inhibitors XL-844, AZD7762, and PF00477736; and

heat shock protein inhibitors geldanamycin and AUY922.

15. The method of claim 13, wherein the modulator of DNA-damage-related immune signalling is selected from cisplatin and ionising radiation.

16. The method of claim 8, wherein at least one of the biomarkers is CXCL10.

17. A method of treating an individual predicted to respond to a modulator of DNA-damage-related immune signalling, comprising treating the individual with the modulator of DNA-damage-related immune signalling, wherein the individual has been predicted to respond to the modulator of DNA-damage-related immune signalling prior to treatment when a combined test score exceeds a threshold score, wherein the combined test score determination has been done by a method comprising:

a. measuring expression levels of at least five biomarkers in a test sample of cancer cells obtained from the individual, wherein the at least five biomarkers are selected from the biomarkers in Table 2B;

b. deriving a combined test score that captures the expression levels; and

c. providing a threshold score comprising information correlating the test score and responsiveness to the modulator of DNA-damage-related immune signalling;

wherein the individual is predicted to respond to the modulator of DNA-damage-related immune signalling when the test score exceeds the threshold score.

18. The method of claim 17, wherein the combined test score captures the expression levels of all 44 biomarkers in Table 2B, and wherein the individual is diagnosed as having a DDRD cancer when the test score exceeds a threshold score calculated using the weights of Table 2B.

19. The method of claim 17, wherein the cancer is selected from melanoma, breast cancer, and ovarian cancer.

20. The method of claim 19, wherein the cancer is associated with one or more mutations in the Fanconi anemia/BRCA pathway.

21. The method of claim 17, wherein the modulator of DNA-damage-related immune signalling is selected from cisplatin and ionising radiation.

22. The method of claim 17, wherein at least one of the biomarkers is CXCL10.

23. A method of predicting response of an individual to, and treating an individual with, a DNA-damage therapeutic agent, comprising:

a. measuring expression levels of at least two biomarkers in a test sample of cancer cells obtained from the individual, wherein at least one biomarker is selected from the group consisting of CXCL10, IDO1, and APOL3;

b. deriving a combined test score that captures the expression levels;

c. providing a threshold score comprising information correlating the test score and responsiveness to a DNA-damage therapeutic agent;

wherein the individual is predicted to respond to a DNA-damage therapeutic agent when the test score exceeds the threshold score; and

d. treating the individual that is so predicted to respond with a DNA-damage therapeutic agent.

24. The method of claim 23, further comprising measuring expression level(s) of one or more additional biomarkers in the test sample wherein the one or more additional biomarkers are selected from the group consisting of CDR1, FYB, TSPAN7, RAC2, KLHDC7B, GRB14, AC138128.1, KIF26A, CD274, CD109, ETV7, MFAP5, OLFM4, PI15, FOSB, FAM19A5, NLRC5, PRICKLE1, EGR1, CLDN10, ADAMTS4, SP140L, ANXA1, RSAD2, ESR1, IKZF3, OR2I1P, EGFR, NAT1, LATS2, CYP2B6, PTPRC, PPP1R1A, and AL137218.1.

25. The method of claim 23, wherein the test score captures the expression levels of all biomarkers from the group consisting of CXCL10, MX1, IDO1, IFI44L, CD2, GBP5, PRAME, ITGAL, LRP4, and APOL3, and wherein the individual is diagnosed as having a DDRD cancer when the test score exceeds the threshold score.

26. The method of claim 23, wherein the cancer is selected from melanoma, breast cancer, and ovarian cancer.

27. The method of claim 26, wherein the cancer is associated with one or more mutations in the Fanconi anemia/BRCA pathway.

28. The method of claim 23, wherein the DNA-damage therapeutic agent comprises one or more substances selected from the group consisting of:

a DNA damaging agent, a DNA repair targeted therapy, an inhibitor of DNA damage signalling, an inhibitor of DNA damage induced cell cycle arrest, a histone deacetylase inhibitor, and a heat shock protein inhibitor.

29. The method of claim 23, wherein the DNA-damage therapeutic agent is a modulator of DNA-damage-related immune signalling.

30. The method of claim 29, wherein the modulator of DNA-damage-related immune signalling is selected from cisplatin and ionising radiation.

31. The method of claim 23, wherein at least one of the biomarkers is CXCL10.