METHOD FOR THE DIAGNOSIS, PROGNOSIS AND TREATMENT OF LUNG CANCER METASTASIS

• US 20150152506A1
• Filed: 06/06/2013
• Published: 06/04/2015
• Est. Priority Date: 06/06/2012
• Status: Active Grant

• Current Assignee: Institucio Catalana De Recerca I Estudis Avancats, Institute for Research in Biomedicine (IRB)
• Original Assignee: Fundacio Catalana De Recerca I Estudis Avancats
• Inventors: Gomis, Roger, Planet, Evarist
• Granted Patent: US 10,006,091 B2
• Time in Patent Office: Days
• US Class Current: 1/1
• CPC Class Codes: A61K 47/548 Phosphates or phosphonates, e.g. bone-seeking phospholipids A61K47/544
• CPC Class Codes: A61P 35/04 specific for metastasis
• CPC Class Codes: C07K 16/2875 against the NGF/TNF superfamily, e.g. CD70, CD95L, CD153, CD154 against NGF C07K16/22, against TNF C07K16/241
• 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 2600/118 Prognosis of disease development
• CPC Class Codes: C12Q 2600/156 Polymorphic or mutational markers
• CPC Class Codes: C12Q 2600/158 Expression markers
• CPC Class Codes: G01N 2333/82 Translation products from oncogenes
• CPC Class Codes: G01N 2800/50 Determining the risk of developing a disease
• 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 33/57423 of lung

Abstract

The present invention relates to a method for the diagnosis or the prognosis of metastasis in lung cancer which comprises determining if the c-MAF gene is amplified in a primary tumor sample. Likewise, the invention also relates to a method for the diagnosis or the prognosis of metastasis in lung cancer, as well as to a method for determining the tendency to develop bone metastasis with respect to metastasis in other organs, which comprise determining the c-MAF gene expression level. Finally, the invention relates to the use of a c-MAF inhibitor as therapeutic target for treating the lung cancer.

Claims

1. An in vitro method for the diagnosis of metastasis in a subject with lung cancer and/or for the prognosis of the tendency to develop metastasis in a subject with lung cancer which comprises

(i) quantifying the c-MAF gene expression level in a tumor sample of said subject and

(ii) comparing the expression level previously obtained with the expression level of said gene in a control sample,

wherein if the expression levels of said gene are increased with respect to the expression levels of said gene in the control sample, then said subject has a positive diagnosis for metastasis or a greater tendency to develop metastasis.

3. The method according to claims 1 or 2, wherein the metastasis is bone metastasis.

4. The method according to claim 3, wherein the bone metastasis is osteolytic metastasis.

11. The method according to any of claims 1, 2 or 5, wherein the quantification of the c-MAF gene expression levels comprises quantifying the messenger RNA (mRNA) of said gene, or a fragment of said mRNA, the complementary DNA (cDNA) of said gene, or a fragment of said cDNA.

12. The method according to claim 11, wherein the expression levels is quantified by means of a quantitative polymerase chain reaction (PCR) or a DNA or RNA array.

13. The method according to any of claims 1, 2 or 5, wherein the quantification of the c-MAF gene expression levels comprises quantifying the levels of protein encoded by said gene or of a variant thereof.

14. The method according to claim 13, wherein the levels of protein is quantified by means of western blot, ELISA or a protein array.

33. A method according to claim 1, wherein the lung cancer is lung adenocarcinoma.

2. An in vitro method for designing a customized therapy for a subject with lung cancer which comprises

(i) quantifying the c-MAF gene expression level in a tumor sample of said subject and

(ii) comparing the expression level previously obtained with the expression level of said gene in a control sample,

wherein if the expression levels are increased with respect to the expression levels of said gene in the control sample, then said subject is susceptible to receive a therapy aiming to prevent an/or treat the metastasis.

5. An in vitro method for designing a customized therapy for a subject with lung cancer with bone metastasis which comprises

(i) quantifying the c-MAF gene expression level in a bone metastatic tumor tissue sample of said subject and

(ii) comparing the expression level obtained in step (i) with the expression level of said gene in a control sample,

wherein if the c-MAF gene expression levels are increased with respect to the expression levels of said gene in the control sample, then said subject is susceptible to receive a therapy aiming to prevent the bone degradation.

6. The method according to claim 5, wherein the agent preventing the bone degradation is selected from the group consisting of a bisphosphonate, a RANKL inhibitor, PTH or PTHLH (including neutralizing antibodies and peptides) or a PRG analog, strontium ranelate, calcitonin, and a cathepsin K inhibitor.

7. The method according to claim 6, wherein the RANKL inhibitor is selected from the group consisting of a RANKL specific antibody and osteoprotegerin.

8. The method according to claim 7, wherein the RANKL specific antibody is denosumab.

9. The method according to claim 6, wherein the bisphosphonate is zoledronic acid.

10. The method according to claim 5, wherein the lung cancer is SCLC or NSCLC.

15. An in vitro method for diagnosing metastasis in a subject with lung cancer and/or for the prognosis of the tendency to develop metastasis in a subject with lung cancer which comprises determining if the c-MAF gene is amplified in a tumor sample of said subject wherein if said gene is amplified, then said subject has a positive diagnosis for metastasis or a greater tendency to develop metastasis.

16. The method according to claim 15, wherein the lung cancer is SCLC or NSCLC.

17. The method according to claim 15, wherein the amplification of the c-MAF gene is determined by means of determining the amplification of the locus 16q22-q24.

18. The method according to claim 15, wherein the amplification of the c-MAF gene is determined by means of using a c-MAF gene-specific probe.

19. The method according to claim 15, wherein the control sample is a tumor tissue sample of lung cancer from a subject who has not suffered metastasis.

20. The method according to claim 15, wherein the amplification is determined by means of in situ hybridization or PCR.

21. The method according to claim 15, wherein the metastasis is bone metastasis.

22. The method according to claim 21, wherein the bone metastasis is osteolytic metastasis.

23. Use of a c-MAF inhibitory agent in the preparation of a medicinal product for treating and/or preventing the bone metastasis from lung cancer.

24. Use according to claim 23, wherein the lung cancer is SCLC or NSCLC.

25. Use according to claim 23, wherein the c-MAF inhibitory agent is selected from the group consisting of a c-MAF specific siRNA, a c-MAF specific antisense oligonucleotide, a c-MAF specific ribozyme, a c-MAF inhibitory antibody, a dominant negative c-MAF variant and a compound from Table 1 or from Table 2.

26. Use of an agent capable of avoiding or preventing bone degradation in the preparation of a medicinal product for the treatment of bone metastasis in a subject suffering lung cancer and has elevated c-MAF levels in a metastatic tumor sample with respect to a control sample.

27. Use according to claim 26, wherein the agent capable of avoiding or preventing bone degradation is selected from the group consisting of a bisphosphonate, a RANKL inhibitor, PTH or PTHLH (including neutralizing antibodies and peptides) or a PRG analog, strontium ranelate, a, an EGFR inhibitor, calcitonin and a cathepsin K inhibitor.

28. Use according to claim 27, wherein the RANKL inhibitor is selected from the group of a RANKL specific antibody and osteoprotegerin.

29. Use according to claim 28, wherein the RANKL specific antibody is denosumab.

30. Use according to claim 27, wherein the bisphosphonate is zoledronic acid.

31. Use according to claim 26, wherein the lung cancer is SCLC or NSCLC.

32. Use according to claim 26, wherein the bone metastasis is osteolytic metastasis.

34. A kit for predicting bone metastasis of a lung cancer in a subject suffering from said cancer, the kit comprising:

a) means for quantifying the expression level of c-MAF in a sample of said subject; and

b) means for comparing the quantified level of expression of c-MAF in said sample to a reference c-MAF expression level.

35. An in vitro method for typing a sample of a subject suffering from lung cancer, the method comprising:

a) providing a sample from said subject;

b) quantifying the expression level of c-MAF in said sample;

c) typing said sample by comparing the quantified expression level of c-MAF to a predetermined reference level of c-MAF expression;

wherein said typing provides prognostic information related to the risk of bone metastasis in said subject.

36. A method for preventing or reducing the risk of bone metastasis in a subject suffering from lung cancer, said method comprising administering to said subject an agent that prevents or reduces bone metastasis, wherein said agent is administered in accordance with a treatment regimen determined from quantifying the expression level of c-MAF in said subject.

37. A method of classifying a subject suffering from lung cancer into cohort, comprising:

a) determining the expression level of c-MAF in a sample of said subject;

b) comparing the expression level of c-MAF in said sample to a predetermined reference level of c-MAF expression; and

c) classifying said subject into a cohort based on said expression level of c-MAF in the sample.