Method for the diagnosis, prognosis and treatment of cancer metastasis

a cancer metastasis and prognosis technology, applied in the field of cancer metastasis diagnosis, prognosis and treatment, can solve the problems of cell change, inhibit expression, and increase the risk of metastatic cancer,

Inactive Publication Date: 2014-10-23
FUNDACIO INST DE RECERCA BIOMEDICA (IRB BARCELONA) +1
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  • Summary
  • Abstract
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  • Application Information

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Benefits of technology

[0011]The authors of this invention have identified a group of genes whose expression is increasing or diminishing in breast tumor samples as a result of changes in the expression of the c-MAF gene. By means of gain-of-function experiments and correlated clinical data the authors have validated the role of these genes, and, in particular, that of the RERG gene, whose expression is inversely related to that of c-MAF, and that of the PTHLH and PODXL genes, whose expression is directly related to the c-MAF expression, such as prognosis markers of ER+ breast cancer metastasizing to the bone.
[0012]Hence, in a first aspect, the invention is related to an in-vitro method for predicting metastatic cancer in a subject, in particular breast, colon, lung, kidney and thyroid cancer, but specifically breast cancer, consisting of determining the expression level in a sample of cancerous tissue of one or more genes whose expression is modulated in response to an increase in the c-MAF expression levels of the said tumor, where the changed expression levels of the aforementioned one or more genes in relation to a standard value are an indication of a high risk of developing metastatic cancer.
[0013]A second aspect of the invention relates to an in-vitro method for the creation of customized therapy for a subject suffering from cancer, in particular breast, colon, lung, kidney or thyroid cancer, but specifically breast cancer, consisting of determining the expression level in a sample of cancerous tissue of one or more genes whose expression is modulated in response to an increase in the c-MAF expression levels of...

Problems solved by technology

Certain chemical messengers such as hormones bind t...

Method used

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  • Method for the diagnosis, prognosis and treatment of cancer metastasis
  • Method for the diagnosis, prognosis and treatment of cancer metastasis
  • Method for the diagnosis, prognosis and treatment of cancer metastasis

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example 1

Selection of Relevant Genes

[0280]An analysis was performed, the purpose of which was to select genes that express in a differential manner in cells derived from a single ER+ breast cancer cell line in response to changes in the levels of expression of c-MAF (FIG. 1B). The genes and functions that were determinative of the bone metastasis program mediated by c-MAF were selected following the below criteria:[0281]i) Genes the expression of which in primary tumors is significantly correlated with the expression of c-MAF.[0282]ii) Genes whose expression is modified with the expression of c-MAF, either when c-MAF is over-expressed (long or short isoform) in MCF7 cells, or when the expression of c-MAF in highly metastatic bone cells derived from MCF7 expressing c-MAF is reduced, and[0283]iii) Genes that are correlated to the expression of MAF in primary tumors and in one of the mentioned cellular conditions in ii) are considered members of the bone metastatic program mediated by c-MAF.

[02...

example 2

[0285]The therapeutic value and prognostic value of genes enriched for the development of bone metastasis.

[0286]The genes enriched in bone metastasis through the experimental system for the selection of metastatic cell populations developed here were evaluated vis-a-vis two different databases containing the expression profiles and the clinical records of 560 primary breast cancer tumors and 58 metastases from patients suffering from breast cancer. These tumors are representative of all of the sub-types of breast cancer and localizations of metastases. Both databases and the related clinical records are available to the public (GSE 2603, 2034, 12276 and 14020).

[0287]The gene expression in ER+ primary tumors and the genes taken from bone metastases demonstrated a significant correlation with a recurrence in bones and metastasis (FIGS. 10 and D).

example 3

In Vivo Functional Validation of the Members of the Program for Bone Metastasis Mediated by c-MAF: PTHLH Gene

[0288]The metastatic PTHLH gene, positive during prior analysis and directly correlated with the expression of c-MAF (FIG. 2), was functionally validated in a metastatic colonization trial in bones in an xenograft experimental model of breast cancer metastasis in mice. The standard approximations / approaches to validate the candidate gene to direct the process of metastasis were the samples of the gain in function in low-metastatic cells. The expression of the PTHLH gene was induced in cells that were moderately metastatic in bone, in vivo, MCF7, that present low levels of expression of the gene, c-MAF responsible for the increase in the endogenous levels of the PTHLH gene.

[0289]In the process for the transduction of the gene, lentiviral systems were used to infect and introduce the expression of the candidate gene in the tumor cells. The functions facilitating the metastasis ...

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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.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS[0001]This application claims the benefit of Spanish Application No. P201330384, filed Mar. 15, 2013, which is incorporated by reference herein in its entirety.REFERENCE TO A SEQUENCE LISTING SUBMITTED ELECTRONICALLY VIA EFS-WEB[0002]The content of the electronically submitted sequence listing (Name: 3190—0130000_SEQLISTING.ascii; Size: 2,257 bytes; and Date of Creation: Mar. 13, 2014) is herein incorporated by reference in its entirety.OBJECTS OF THE INVENTION[0003]This invention relates to methods to determine the likelihood a subject suffering from cancer, in particular breast, colon, lung, kidney or thyroid cancer, will develop a metastasis, in addition to methods for the creation of customized therapies for a subject suffering from cancer, in particular breast, colon, lung, kidney or thyroid cancer. Such methods consist of determining the expression level of a set of genes whose expression is related to the c-MAF gene expression. The inven...

Claims

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Application Information

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IPC IPC(8): C12Q1/68C07K16/32A61K38/17C12N15/113
CPCC12Q1/6886A61K38/17C07K16/32C12N15/1135C12Q2600/118C12Q2600/158C12Q2600/106A61P35/00A61P35/04Y10T436/143333C12N2310/14C12N2320/30C12N2310/11
Inventor GOMIS, ROGERARNAL, ANNATARRAGONA, MARIAPAVLOVIC, MILICAPLANET, EVARIST
Owner FUNDACIO INST DE RECERCA BIOMEDICA (IRB BARCELONA)
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