Claims for Patent: 10,119,171

Summary for Patent: 10,119,171

Title:	Method for the diagnosis, prognosis and treatment of prostate cancer metastasis
Abstract:	The present invention relates to a method for the diagnosis or the prognosis of metastasis, relapse or recurrence in prostate 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, relapse or recurrence in prostate 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 expression level. Finally, the invention relates to the use of a c-MAF inhibitor as therapeutic target for treating the prostate cancer.
Inventor(s):	Gomis; Roger (Barcelona, ES), Jean-Mairet; Joel (Barcelona, ES)
Assignee:	InBioMotion S.L. (Barcelona, ES)
Application Number:	15/183,419
Patent Claims:	1. An in vitro method for the diagnosis of metastasis in a subject with prostate cancer and/or for the prognosis of the tendency to develop metastasis, relapse or recurrence in a subject with prostate cancer, comprising: (i) contacting a prostate tumor sample from the subject with an antibody to quantify c-MAF gene expression level or amplification, and (ii) comparing the expression level or amplification obtained in (i) with the expression level or amplification of the c-MAF gene in a control sample, wherein the antibody comprises a heavy chain CDR1 of SEQ ID NO: 21, a heavy chain CDR2 of SEQ:ID NO: 22, a heavy chain CDR3 of SEQ ID NO: 23, a light chain CDR1 of SEQ ID NO: 18, a light chain CDR2 of SEQ ID NO: 19, and a light chain CDR3 of SEQ ID NO: 20, wherein if the expression level or amplification of the c-MAF gene in said tumor sample is increased with respect to the expression level or amplification of the c-MAF gene in the control sample, then said subject has a positive diagnosis for metastasis, relapse or recurrence or a greater tendency to develop metastasis, relapse or recurrence. 2. An in vitro method for designing a customized therapy for a subject with prostate cancer, comprising: (i) contacting a prostate tumor sample from the subject with an antibody to quantify c-MAF gene expression level or amplification, and (ii) comparing the expression level or amplification obtained in (i) with the expression level or amplification of the c-MAF gene in a control sample, wherein the antibody comprises a heavy chain CDR1 of SEQ ID NO: 21, a heavy chain CDR2 of SEQ ID NO: 22, a heavy chain CDR3 of SEQ ID NO: 23, a light chain CDR1 of SEQ ID NO: 18, a light chain CDR2 of SEQ ID NO: 19, and a light chain CDR3 of SEQ ID NO: 20, wherein if the expression level or amplification of the c-MAF gene in the tumor sample is increased with respect to the expression level or amplification of the c-MAF gene in the control sample, then said subject is susceptible to receive a therapy intended to prevent, inhibit and/or treat metastasis, relapse or recurrence of the cancer or a therapy intended to prevent or inhibit bone degradation. 3. The method according to claim 1, wherein the metastasis is bone metastasis. 4. The method according to claim 3, wherein the bone metastasis is osteolytic metastasis. 5. The method according to claim 2, wherein the therapy intended to prevent, inhibit and/or treat metastasis, relapse or recurrence of the cancer is selected from the group consisting of: a c-MAF inhibitory agent; systemic treatments including but not limited to chemotherapy, hormone therapy, and immunotherapy; radiotherapy; surgery; an mTor inhibitor; a Src kinase inhibitor; a CCR5 antagonist; a COX-2 inhibitor; and Alpharadin; and/or wherein the therapy intended to prevent or inhibit bone degradation is selected from the group consisting of: a bisphosphonate, a RANKL inhibitor, a PTH or PTHLH inhibitor, 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. 6. The method according to claim 5, wherein the RANKL inhibitor is selected from the group consisting of: a RANKL specific antibody, a RANKL-specific nanobody, and osteoprotegerin. 7. The method according to claim 6, wherein the RANKL specific antibody is denosumab or the RANKL specific nanobody is ALX-0141. 8. The method according to claim 5, wherein the bisphosphonate is zoledronic acid or the dual MET and VEGFR2 inhibitor is Cabozantinib. 9. The method according to claim 1, wherein the amplification of the c-MAF gene is determined by means of determining the amplification of the locus 16q22-q24. 10. The method according to claim 2, wherein the metastasis is bone metastasis. 11. A method for treating, inhibiting, reducing the risk of and/or preventing bone metastasis, relapse or recurrence from prostate cancer in a subject suffering prostate cancer, comprising: (i) contacting a prostate tumor sample from subject with an antibody to quantify c-MAF gene expression level or amplification, (ii) comparing the expression level or amplification obtained in (i) with the expression level or amplification of the c-MAF gene in a control sample, wherein if the expression level or amplification or the c-MAF gene in the tumor sample is increased with respect to the expression level or amplification of the c-MAF gene in the control sample, then the subject is susceptible to receive a c-MAF inhibitory agent and/or a therapy intended to prevent or inhibit bone degradation, and (iii) administering a c-MAF inhibitory agent to the subject 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, and a c-MAF specific alphabody, and/or administering a therapy intended to prevent or inhibit bone degradation to the subject selected from the group consisting of: a bisphosphonate, a RANKL, inhibitor, a PTH or PTHLH inhibitor, a PRG analog, strontium ranelate, a DKK-1 inhibitor, a dual MET and VEGFR2 inhibitor, an estrogen receptor modulator, an EGFR inhibitor, calcitonin, Radium-223, and a cathepsin K inhibitor, wherein the antibody comprises a heavy chain CDR1 of SEQ ID NO: 21, a heavy chain CDR2 of SEQ ID NO: 22, a heavy chain CDR3 of SEQ ID NO: 23, a light chain CDR1 of SEQ ID NO: 18, a light chain CDR2 of SEQ ID NO: 19, and a light chain CDR3 of SEQ ID NO: 20. 12. The method according to claim 11, wherein the RANKL inhibitor is selected from the group consisting of: a RANKL specific antibody, a RANKL specific nanobody, and osteoprotegerin. 13. The method according to claim 12, wherein the RANKL specific antibody is denosumab or the RANKL specific nanobody is ALX-0141. 14. The method according to claim 11, wherein the bisphosphonate is zoledronic acid or the dual MET and VEGFR2 inhibitor is Cabozantinib. 15. A kit for predicting bone metastasis, relapse or recurrence of a prostate cancer in a subject suffering from said cancer or for determining a therapy for a subject suffering prostate cancer, comprising: a) means for quantifying the expression level of c-MAF in a tumor sample of said subject; b) means for comparing the quantified level of expression of c-MAF in said sample to a reference c-MAF expression level, and, optionally, c) means for determining a therapy for preventing, inhibiting and/or reducing bone metastasis, relapse or recurrence in said subject based on the comparison of the quantified expression level to the reference c-MAF expression level, wherein the means for quantifying the expression level of c-MAF is an antibody comprising a heavy chain CDR1 of SEQ. ID NO: 21, a heavy chain CDR2 of SEQ ID NO: 22, a heavy chain CDR3 of SEQ ID NO: 23, a light chain CDR1 of SEQ 1D NO: 18, a light chain CDR2 of SEQ ID NO: 19, and a light chain CDR3 of SEQ ID NO: 20. 16. An in vitro method for typing a sample of a subject suffering from prostate cancer, comprising: (i) providing a tumor sample from said subject; (ii) contacting lwith an antibody to quantify the expression level or amplification of c-MAF; (iii) typing said sample by comparing the quantified expression level or amplification of c-MAF to a predetermined reference level of c-MAF expression or amplification; wherein the antibody comprises a heavy chain CDR1 of SEQ ID NO: 21, a heavy chain CDR2 of SEQ ID NO: 22, a heavy chain CDR3 of SEQ ID NO: 23, a light chain CDR1 of SEQ ID NO: 18, a light chain CDR2 of SEQ ID NO: 19, and a light chain CDR3 of SEQ ID NO: 20, wherein said typing provides prognostic information related to the risk of bone metastasis, relapse or recurrence in said subject. 17. A method of classifying a subject suffering from prostate cancer into a cohort, comprising: a) contacting a prostate tumor sample from the subject with an antibody to quantify c-MAF gene expression level or amplification; b) comparing the expression level or amplification of c-MAF in said sample to a predetermined reference level of c-MAF expression or amplification; and c) classifying said subject into a cohort based on said expression level or amplification of c-MAF in said sample, wherein the antibody comprises a heavy chain CDR1 of SEQ ID NO: 21, a heavy chain CDR2 of SEQ ID NO: 22, a heavy chain CDR3 of SEQ ID NO: 23, a light chain CDR1 of SEQ ID NO: 18, a light chain CDR2 of SEQ ID NO: 19, and a light chain CDR3 of SEQ ID NO: 20. 18. The method according to claim 17, wherein said cohort comprises at least one other individual who has been determined to have a comparable expression level or amplification of c-MAF in comparison to said reference expression level or amplification. 19. The method according to claim 17, wherein said expression level or amplification of c-MAF in said sample is increased relative to said predetermined reference expression level or amplification, and wherein members of the cohort are classified as having increased risk of bone metastasis, relapse or recurrence. 20. The method according to claim 17, wherein the cohort is for conducting a clinical trial.

Details for Patent 10,119,171

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Amgen, Inc.	PROLIA	denosumab	Injection	125320	06/01/2010		2032-10-12
Amgen, Inc.	XGEVA	denosumab	Injection	125320	11/18/2010		2032-10-12