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 . An in vitro method for predicting the risk of metastasis in a subject suffering breast cancer which comprises determining the expression level of one or more genes whose expression is modulated in response to an increase or decrease in the level of the expression of c-MAF in a sample of said subject, wherein the changed expression levels of said one or more genes with respect to a reference value is indicative of an increased risk of the development of metastasis, and wherein the expression of the genes is determined by determining the mRNA expression or the expression of the polypeptide encoded by the gene. 
     
     
         2 . The method according to  claim 1 , wherein said one or more genes whose expression is modulated in response to an increase in the level of expression of c-MAF is selected from Table 1 or Table 2, wherein the genes in Table 1 are increased in response to an increase in expression of c-MAF and the genes in Table 2 are decreased in response to an increase in expression of c-MAF. 
     
     
         3 . The method according to  claim 2 , wherein the one or more genes whose expression is modulated in response to an increase in the level of expression of c-MAF is selected from the group consisting of PTHLH, PODXL, NAV-3, BCL11A, CD36, and RERG. 
     
     
         4 . An in vitro method for designing a personalized therapy for a subject suffering breast cancer, wherein the subject is susceptible to receive a therapy aiming to prevent and/or treat metastasis if the subject has an altered expression of one or more genes whose expression is modulated in response to an increase or decrease in the level of c-MAF expression, and wherein the expression of the genes is determined by determining the mRNA expression or the expression of the polypeptide encoded by the gene. 
     
     
         5 . The method according to  claim 4 , wherein the one or more genes whose expression is modulated in response to an increase in the level of expression of c-MAF is selected from Table 1 or Table 2, and wherein the genes in Table 1 are increased in response to an increase in expression of c-MAF and the genes in Table 2 are decreased in response to an increase in expression of c-MAF. 
     
     
         6 . The method according to  claim 5 , wherein the one or more genes whose expression is modulated in response to an increase in the levels of expression of c-MAF is selected from the group consisting of PTHLH, PODXL, NAV-3, BCL11A, CD36, and RERG. 
     
     
         7 . The method according to  claim 1  or  4 , in which the breast cancer is an ER+ cancer or a triple-negative cancer. 
     
     
         8 . The method according to any of the  claim 1  or  4  in which the metastasis is bone metastasis. 
     
     
         9 . (canceled) 
     
     
         10 . (canceled) 
     
     
         11 . (canceled) 
     
     
         12 . A method for the treatment and/or prevention of breast cancer in a subject comprising administering an agent capable of inhibiting the expression of a gene or the activity of the expression product of a gene whose expression is modulated in response to an increase or a decrease in the level of c-MAF expression, wherein the subject has an altered expression of one or more genes whose expression is modulated in response to an increase or a decrease in the level of c-MAF expression, wherein the expression of the gene in breast cancer tumor cells increases in response to an increase in the level of expression of c-MAF in said cells or decreases in response to a decrease in the level of expression of c-MAF in said cells. 
     
     
         13 . The method of  claim 12 , in which the agent that inhibits the expression of a gene is selected from an RNAi specific to said gene, an antisense oligonucleotide specific to said gene, a ribozyme specific for said gene an inhibitor antibody specific for an expression product of the gene, a dominant-negative variant of an expression product of the gene and an inhibitory peptide from an expression product of the gene. 
     
     
         14 . The method of  claim 12 , wherein the one or more genes is selected from Table 1. 
     
     
         15 . The method of  claim 14 , wherein the one or more genes is selected from the group consisting of the PHTLH gene or the PODXL gene. 
     
     
         16 . A method for the treatment and/or prevention of breast cancer in a subject comprising administering an agent capable of stimulating the expression of a gene or the activity of the protein product of a gene whose expression is modulated in response to the level of c-MAF expression, wherein the subject has an altered expression of one or more genes whose expression is modulated in response to the level of c-MAF expression wherein the expression of the gene in breast cancer tumor cells decreases in response to an increase in the level of expression of c-MAF in said cells or increases in response to a decrease in the level of expression of c-MAF in said cells. 
     
     
         17 . The method of  claim 16 , wherein the agent that stimulates the expression of the gene is selected from a polynucleotide that encodes the gene or a polypeptide that encodes the gene. 
     
     
         18 . The method of  claim 16  in which the gene is selected from the genes in Table 2. 
     
     
         19 . The method of  claim 18  in which the gene whose expression decreases in response to an increase in c-MAF expression level in a breast tumor is the RERG gene. 
     
     
         20 . The method of  claims 12  or  16 , in which the breast cancer is ER+ cancer or triple negative cancer. 
     
     
         21 . The method of  claims 12  or  16 , in which the metastasis is bone metastasis. 
     
     
         22 . The method of  claim 21 , in which the bone metastasis is oseolytic metastasis. 
     
     
         23 . An in vitro method for the identification of a gene that predicts breast cancer metastasis comprising:
 (i) determining the expression levels of a candidate gene and of c-MAF in a breast cancer primary tumor sample and   (ii) determining the change in the expression level of said gene in a population of breast cancer cells in response to a modulation to the expression of the c-MAF gene,   wherein if the expression levels of said gene are statistically significantly correlated to the expression of c-MAF in the breast cancer primary tumor sample, and the change in the expression levels of the gene in response to the modulation of c-MAF gene expression is statistically significantly then the gene is a marker for predicting to metastasis in a subject.   
     
     
         24 . The method according to  claim 23 , wherein the expression of the candidate gene in step (i) is directly correlated with the level of c-MAF in the primary tumor sample and if the change in the expression levels in response to modulation of c-MAF gene expression is directly correlated to said modulation, this is indicative that high levels of said gene are indicative of propensity to metastasis. 
     
     
         25 . The method according to  claim 23 , wherein the expression of the candidate gene in step (i) is inversely correlated with the levels of c-MAF in the primary tumor sample and if the change in the expression levels in response to modulation of c-MAF gene expression is inversely correlated to said modulation, this is indicative that the reduced levels of said gene are indicative of propensity to metastasis. 
     
     
         26 . The method according to  claim 23 , wherein the modulation of the c-MAF expression level is an increase in the c-MAF expression level. 
     
     
         27 . The method according to  claim 26  in which the increase in expression is an increase in the cell population of the c-MAF short isoform and/or the long isoform. 
     
     
         28 . The method according to  claim 23 , wherein the modulation of the c-MAF expression level is a decrease in the c-MAF expression level. 
     
     
         29 . The method according to  claim 28 , wherein c-MAF short isoform and/or the c-MAF long isoform expression is decreased. 
     
     
         30 . The method according to  claim 23 , wherein the breast cancer cells and/or the primary tumor are ER+ or triple negative. 
     
     
         31 . The method according to  claim 23 , wherein the metastasis is bone metastasis. 
     
     
         32 . (canceled) 
     
     
         33 . (canceled)