Method for the diagnosis, prognosis and treatment of cancer metastasis

Abstract

This study describes a method to determine the likelihood of the development of metastasis in a subject suffering from cancer, in addition to a method to design a customized therapy in a subject suffering from cancer, in particular breast, colon, lung, kidney and thyroid cancer, based on the determination of the expression level of one or more genes whose expression is modulated by an increase in c-MAF expression. It also describes a method for the identification of marker genes with a propensity for metastatic cancer based on inducing the modulation of the c-MAF expression Finally, the use of PTHLH and PODXL inhibitors and RERG activators in the treatment and/or prevention of the cancer, in particular breast, colon, lung, kidney and thyroid cancer.

1 .- 33 . (canceled) 
     
     
         34 . A method for the treatment and/or prevention of breast cancer metastasis in a subject comprising
 (i) quantifying an expression level of c-MAF in a breast cancer tumor sample of the subject,   (ii) quantifying an expression level of a gene whose expression level is increased in response to an increase in the level of expression of c-MAF in a breast cancer tumor sample of the subject,   (iii) determining that the subject has an increased expression level of c-MAF and of the gene whose expression level is increased in response to an increase in the level of expression of c-MAF,   (iv) administering to the subject an agent capable of inhibiting the activity of the expression product of the gene whose expression level is increased in response to an increase in the level of c-MAF expression,   wherein the agent capable of inhibiting the activity of the expression product of the gene whose expression level is increased in response to an increase in the level of c-MAF expression is selected from the group consisting of: an RNAi specific to the gene, an antisense oligonucleotide specific to the gene, a ribozyme specific for the gene, an inhibitor antibody specific for an expression product of the gene whose expression level is increased in response to an increase in the level of expression of c-MAF, a dominant-negative variant of an expression product of the gene whose expression level is increased, an inhibitory peptide from an expression product of the gene of interest, siRNA, a DNA enzyme,   and   wherein the gene whose expression level is increased in response to an increase in the level of expression of c-MAF is VTCN1.   
     
     
         35 . The method of  claim 34 , wherein the breast cancer is ER+ cancer or triple negative cancer. 
     
     
         36 . The method of  claim 34 , wherein the metastasis is bone metastasis. 
     
     
         37 . The method of  claim 36 , wherein the bone metastasis is osteolytic bone metastasis. 
     
     
         38 . The method of  claim 34 , wherein the increase in the level of c-MAF expression is an increase in the level of expression of the short isoform of c-MAF. 
     
     
         39 . The method of  claim 34 , wherein the increase in the level of c-MAF expression is an increase in the level of expression of the long isoform of c-MAF. 
     
     
         40 . The method of  claim 34 , wherein the subject is human. 
     
     
         41 . The method of  claim 34 , wherein quantifying the expression level of the gene whose expression level is increased in response to an increase in the level of expression of c-MAF in the breast cancer tumor sample of the subject occurs before quantifying the expression level of c-MAF in the breast cancer tumor sample of the subject. 
     
     
         42 . The method of  claim 34 , wherein the breast cancer tumor sample has expression levels of c-MAF of at least 1.1 times, 1.5 times, 5 times, 10 times, 20 times, 30 times, 40 times, 50 times, 60 times, 70 times, 80 times, 90 times, 100 times or greater compared to a reference value and of the gene whose expression level is increased in response to an increase in the level of expression of c-MAF of at least 1.1 times, 1.5 times, 5 times, 10 times, 20 times, 30 times, 40 times, 50 times, 60 times, 70 times, 80 times, 90 times, 100 times or greater compared to a reference value. 
     
     
         43 . An in vitro method for predicting metastasis in a subject having breast cancer which comprises:
 (i) quantifying an expression level of c-MAF in a breast cancer tumor sample of the subject,   (ii) quantifying an expression level of a gene whose expression level is increased in response to an increase in the level of expression of c-MAF in a breast cancer tumor sample of the subject,   (iii) determining that the subject has an increased expression level of c-MAF and of the gene whose expression level is increased in response to an increase in the level of expression of c-MAF,   wherein the increased expression level of c-MAF and of the gene whose expression level is increased in response to an increase in the level of expression of c-MAF is indicative of an increased risk of the development of metastasis, wherein the gene whose expression level is increased in response to an increase in the level of expression of c-MAF is VTCN1.   
     
     
         44 . The method according to  claim 43 , wherein the breast cancer is an ER+ cancer or a triple-negative cancer. 
     
     
         45 . The method according to  claim 43 , wherein the metastasis is bone metastasis. 
     
     
         46 . The method of  claim 45 , wherein the bone metastasis is osteolytic bone metastasis. 
     
     
         47 . The method of  claim 43 , wherein quantifying the expression level of the gene whose expression level is increased in response to an increase in the level of expression of c-MAF in the breast cancer tumor sample of the subject occurs before quantifying the expression level of c-MAF in the breast cancer tumor sample of the subject. 
     
     
         48 . An in vitro method for designing a personalized therapy for a subject having breast cancer comprising
 (i) quantifying an expression level of c-MAF in a breast cancer tumor sample of the subject,   (ii) quantifying an expression level of a gene whose expression level is increased in response to an increase in the level of expression of c-MAF in a breast cancer tumor sample of the subject,   (iii) determining that the subject has an increased expression level of c-MAF and of the gene whose expression level is increased in response to an increase in the level of expression of c-MAF,   (iv) administering to the subject an agent capable of inhibiting the activity of the expression product of the gene whose expression level is increased in response to an increase in the level of c-MAF expression,   wherein the agent capable of inhibiting the activity of the expression product of the gene whose expression level is increased in response to an increase in the level of c-MAF expression is selected from the group consisting of: an RNAi specific to the gene, an antisense oligonucleotide specific to the gene, a ribozyme specific for the gene, an inhibitor antibody specific for an expression product of the gene whose expression level is increased in response to an increase in the level of expression of c-MAF, a dominant-negative variant of an expression product of the gene, an inhibitory peptide from an expression product of the gene of interest, siRNA, a DNA enzyme, and   wherein the gene whose expression level is increased in response to an increase in the level of expression of c-MAF is VTCN1.   
     
     
         49 . The method according to  claim 48 , wherein the breast cancer is an ER+ cancer or a triple-negative cancer. 
     
     
         50 . The method according to  claim 48 , wherein the metastasis is bone metastasis. 
     
     
         51 . The method of  claim 50 , wherein the bone metastasis is osteolytic bone metastasis. 
     
     
         52 . The method of  claim 48 , wherein quantifying the expression level of the gene whose expression level is increased in response to an increase in the level of expression of c-MAF in the breast cancer tumor sample of the subject occurs before quantifying the expression level of c-MAF in the breast cancer tumor sample of the subject.