Method for the prognosis and treatment of cancer metastasis
The present invention relates to a method for the prognosis of bone metastasis in triple negative (including basal-like) breast cancer or, alternatively, ER+ breast cancer (including luminal A and B) which comprises determining if the c-MAF gene is amplified in a primary tumor sample. Likewise, the invention also relates 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, amplification or translocation. The invention also relates to a method for predicting early bone metastasis in a subject suffering breast cancer. The invention also relates to a c-MAF inhibitor as therapeutic agent for use in the treatment of triple negative (including basal-like) breast cancer metastasis or, alternatively, ER+ breast cancer (including luminal A and B) metastasis. The invention relates to kits for predicting bone metastasis and predicting the clinical outcome of a subject suffering from bone metastasis. Finally, the invention relates to a method for typing of a subject suffering breast cancer and for classifying a subject from breast cancer into a cohort.
1. An in vitro method for diagnosing a subject with an increased risk of bone metastasis or recurrence of a triple negative (including basal-like) breast cancer in a subject suffering said cancer and treating said subject to inhibit or prevent said bone metastasis or recurrence, comprising detecting amplification and/or gain of the c-MAF gene in a sample of said subject relative to a reference gene copy number, wherein an amplification and/or gain of the c-MAF gene with respect to said reference gene copy number is indicative of increased risk of developing bone metastasis or recurrence, and administering a therapeutically effective amount of a c-MAF inhibitor, a therapy aiming to prevent and/or treat bone metastasis selected from the group consisting of an mTor inhibitor, a Src kinase inhibitor, a COX-2 inhibitor, a CCR-5 antagonist and/or Radium-223, and/or an agent capable of avoiding and/or preventing bone degradation to said subject with an increased risk of bone metastasis or recurrence.
2. An in vitro method for diagnosing a subject with an increased risk of bone metastasis or recurrence of a triple negative (including basal-like) breast cancer in a subject suffering said cancer and treating said subject to inhibit or prevent said bone metastasis or recurrence, comprising detecting translocation of the c-MAF gene in a sample of said subject, wherein a translocation of the c-MAF gene is indicative of an increased risk of developing bone metastasis or recurrence, and administering a therapeutically effective amount of a c-MAF inhibitor, a therapy aiming to prevent and/or treat bone metastasis selected from the group consisting of an mTor inhibitor, a Src kinase inhibitor, a COX-2 inhibitor, a CCR-5 antagonist and/or Radium-223, and/or an agent capable of avoiding and/or preventing bone degradation to said subject with an increased risk of bone metastasis or recurrence.
3. The method according to any one of claims 1 - 2 , wherein the bone metastasis is osteolytic metastasis.
4. An in vitro method for predicting the clinical outcome of a subject suffering triple negative (including basal-like) breast cancer and further treating said subject, comprising detecting amplification and/or gain of the c-MAF gene in a sample of said subject relative to a reference gene copy number, wherein an amplification and/or gain of the c-MAF gene with respect to said reference gene copy number is indicative of a poor clinical outcome, and administering a therapeutically effective amount of a c-MAF inhibitor, a therapy aiming to prevent and/or treat bone metastasis selected from the group consisting of an mTor inhibitor, a Src kinase inhibitor, a COX-2 inhibitor, a CCR-5 antagonist and/or Radium-223, and/or an agent capable of avoiding and/or preventing bone degradation to said subject.
5. An in vitro method for predicting the clinical outcome of a subject suffering from triple negative (including basal-like) breast cancer and further treating said subject comprising detecting translocation of the c-MAF gene in a sample of said subject, wherein a translocation of the c-MAF gene is indicative of a poor clinical outcome, and administering a therapeutically effective amount of a c-MAF inhibitor, a therapy aiming to prevent and/or treat bone metastasis selected from the group consisting of an mTor inhibitor, a Src kinase inhibitor, a COX-2 inhibitor, a CCR-5 antagonist and/or Radium-223, and/or an agent capable of avoiding and/or preventing bone degradation to said subject.
6. The method of either of claims 2 and 5 , wherein locus 16q23 or 16q22-q24 is translocated.
7. The method of any of claim 2 or 5 , wherein locus 16q23 or 16q22-q24 is translocated to chromosome 14 at locus 14q32.
8. The method of any of claim 2 or 5 , comprising further determining if the c-MAF gene is amplified/gained in the sample of the subject suffering said cancer relative to a reference gene copy number wherein an amplification and/or gain of the c-MAF gene with respect to said reference gene copy number is indicative of increased risk of developing bone metastasis.
9. The method according to any of claim 1 , 2 , 4 or 5 , wherein the amplification and/or gain and translocation of the c-MAF gene is determined by means of determining the amplification or translocation of the locus 16q23 or 16q22-q24.
10. The method according to any of claim 1 , 2 , 4 , or 5 , wherein the amplification and/or gain or the translocation of the c-MAF gene is determined by means of using a c-MAF gene-specific probe.
11. The method according to any of claim 1 , 2 , 4 , or 5 , wherein the reference gene copy number is the gene copy number in a tumor tissue sample of triple negative breast cancer from a subject who has not suffered metastasis.
12. The method of any of claim 1 , 2 , 4 or 5 , comprising further determining if the subject sample is polyploid for the c-MAF gene.
13. The method according to claim 1 , 2 , 4 or 5 , wherein said 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 or nanobody, a dominant negative c-MAF variant, a compound from Table 1 or from Table 2, catalytic RNAs, DNA enzymes, inhibitory antibodies, inhibitory peptides, a c-MAF specific small molecule, a c-MAF specific antibody, a c-MAF specific antibody-like molecule, a c-MAF specific structurally constrained (cyclical) peptide, a c-MAF specific stapled peptide, or a c-MAF specific alphabody.
14. The method according to claim 1 , 2 , 4 or 5 , wherein the agent preventing the bone degradation is selected from the group consisting of a bisphosphonate, a RANKL inhibitor, a PTH or a PTHLH inhibitor or a PRG analog, strontium ranelate, a DKK-1 inhibitor, a dual MET and VEGFR2 inhibitor, an estrogen receptor modulator, calcitonin, Radium-223 and a cathepsin K inhibitor.
15. The method according to claim 14 , wherein the RANKL inhibitor is selected from the group consisting of a RANKL specific antibody, a RANKL-specific nanobody and osteoprotegerin, the bisphosphonate is zoledronic acid, the dual MET and VEGFR2 inhibitor is Cabozantinib, and/or the Radium-223 is alpharadin.
16. The method according to claim 15 , wherein the RANKL specific antibody is denosumab and/or the RANKL specific nanobody is ALX-0141.
17. The method of any one of claim 1 , 2 , 4 or 5 , wherein the mTor inhibitor is Everolimus, the Src kinase inhibitor is dasatinib and/or a second treatment is used in combination with the COX-2 inhibitor.
18. The method of claim 1 , 2 , 4 or 5 , wherein the c-MAF amplification and/or gain or the translocation is quantified by means of western blot, ELISA, FISH, immunohistochemistry or a protein array.
19. The method of claim 1 or 2 , wherein the subject is diagnosed with an increased risk of bone metastasis.