EP2872645A1 - Method and kit for predicting or monitoring the response of a cancer patient to chemotherapy, based on measuring the expression level of tmem45a gene. - Google Patents

Method and kit for predicting or monitoring the response of a cancer patient to chemotherapy, based on measuring the expression level of tmem45a gene.

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Publication number
EP2872645A1
EP2872645A1 EP13727840.4A EP13727840A EP2872645A1 EP 2872645 A1 EP2872645 A1 EP 2872645A1 EP 13727840 A EP13727840 A EP 13727840A EP 2872645 A1 EP2872645 A1 EP 2872645A1
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EP
European Patent Office
Prior art keywords
cancer
tmem45a
gene
sample
measuring
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EP13727840.4A
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German (de)
French (fr)
Inventor
Carine Michiels
Lionel FLAMANT
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Facultes Universitaires Notre Dame de la Paix
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Facultes Universitaires Notre Dame de la Paix
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    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
    • C12Q1/68—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving nucleic acids
    • C12Q1/6876—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes
    • C12Q1/6883—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for diseases caused by alterations of genetic material
    • C12Q1/6886—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for diseases caused by alterations of genetic material for cancer
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q2600/00—Oligonucleotides characterized by their use
    • C12Q2600/158—Expression markers

Definitions

  • the present invention is in the field of cancer diagnostic in relation to TMEM45A expression, and of associated treatments.
  • efflux pump such as the P-glycoprotein encoded by the MDR1 gene or proteins from ABC (ATP-binding cassette) transporter family, which expulses the chemotherapeutic drug out of the tumor cells represents a paradigm of therapy resistance.
  • hypoxia can either promote apoptosis and cell death or contrariwise induce cell growth and survival by provoking an adaptive response.
  • tumor hypoxia has been associated with resistance to chemotherapy and radiotherapy, with tumor progression, aggressiveness and metastasis, and therefore with an increased probability of tumor recurrence.
  • TMEM45A protein The function of TMEM45A protein is almost unknown, and nothing is known about its cellular localization .
  • TMEM45A was found upregulated in hypoxia in umbilical cord blood CD133+ cells.
  • a first aspect of the present invention is a method for predicting the response of a human patient (suffering of a cancer) to a chemotherapy treatment (such as Taxol or etoposide) against this cancer, (this method) comprising the step of measuring the expression level of TMEM45A gene in a sample (e.g. a tumor sample) consisting essentially of cancer cells obtained from this human patient suffering of cancer.
  • a chemotherapy treatment such as Taxol or etoposide
  • a related aspect of the present invention is a method for monitoring the response of a human patient (suffering of cancer) to a chemotherapy (such as Taxol or etoposide) treatment against this cancer, (this method) comprising the step of measuring the expression level of TMEM45A gene in a sample (e.g. a tumor sample) consisting essentially of cancer cells obtained from this human patient suffering of cancer.
  • a chemotherapy such as Taxol or etoposide
  • Another related aspect of the present invention is a method for prognosticating the outcome of a cancer in a human patient comprising the step of measuring the expression level of TMEM45A gene in a sample (e.g. a tumor sample) consisting essentially of cancer cells obtained from this human patient suffering of cancer.
  • a sample e.g. a tumor sample
  • the cancer is a solid tumor cancer, more preferably selected from the group consisting of breast cancer, lung cancer, colon cancer, head and neck cancer, pancreas cancer, liver cancer, kidney cancer, brain cancer, thyroid cancer, ovarian cancer, sarcoma and melanoma, being more still preferably breast cancer, head and neck cancer, lung cancer or kidney cancer.
  • these methods further comprise the step of measuring the expression level of TMEM45A gene in a non-cancer sample consisting of the original and/or native non-cancer cells and possibly the step of comparing the expression level in the cancer cells and in the non cancer cells, possibly wherein this non cancer sample is obtained from the human patient suffering of cancer.
  • a high expression level of TMEM45A gene corresponds to a ratio of TMEM45A gene expression in the cancer sample being of at least 2-fold, preferably at least 3-fold or even at least 10-fold higher than in the non- cancer sample.
  • Such a high expression level represents a worse prognosis and/or a resistance towards chemotherapeutic agents (such as Taxol or etoposide) .
  • the chemotherapy treatment is Paclitaxel (Taxol) or etoposide.
  • these methods further comprise the step of measuring the expression level of at least another (1, 2, 3, 4, 5 or even all the) gene(s) selected from Table 1, preferably at least SPAG4 gene, in the sample consisting essentially of cancer cells, and possibly also in the sample consisting of the original and/or native non-cancer cells .
  • Another related aspect of the present invention is a diagnostic kit comprising tools for measuring the expression of TMEM45A gene.
  • this kit comprises tools for measuring the expression level of less than 100 other genes than TMEM45A gene.
  • this kit further comprises tools for measuring the expression level of at least another (1, 2, 3, 4, 5 or even all the) gene(s) selected from Table 1, preferably at least SPAG4 gene.
  • this kit consists essentially of tools for measuring the expression of TMEM45A gene (and possibly of gene(s) from Table 1) .
  • kits of the present invention for prognosticating the outcome of a cancer in a human patient, or for predicting the response to a chemotherapy treatment of a cancer in a human patient, and/or for monitoring the response to a chemotherapy treatment of a cancer in a human patient.
  • This use is preferably applied on (genes and/or mRNA and/or proteins isolated from) a solid tumor cancer, preferably selected from the group consisting of breast cancer, lung cancer, colon cancer, pancreas cancer, head and neck cancer, liver cancer, kidney cancer, brain cancer, thyroid cancer, ovarian cancer, sarcoma and melanoma, being more preferably breast cancer, lung cancer, head and neck cancer or kidney cancer.
  • a solid tumor cancer preferably selected from the group consisting of breast cancer, lung cancer, colon cancer, pancreas cancer, head and neck cancer, liver cancer, kidney cancer, brain cancer, thyroid cancer, ovarian cancer, sarcoma and melanoma, being more preferably breast cancer, lung cancer, head and neck cancer or kidney cancer.
  • Another related aspect of the present invention is chemotherapy (such as Taxol or etoposide) for use in a human patient suffering of a cancer, wherein TMEM45A gene expression in a cancer sample is less than 2- fold higher than in original and/or native non-cancer sample .
  • the preferred chemotherapy treatment are selected from the group consisting of Paclitaxel (taxol) and etoposide.
  • anthracyclines and also mitomycin C or camptothecin
  • TMEM45A can be used in patients having a high expression (a ratio of expression of more than 2- fold, preferably more than 3-fold) level of TMEM45A.
  • These chemotherapy treatments are preferably used for the treatment of solid tumor cancers, preferably selected from the group consisting of breast cancer, lung cancer, colon cancer, pancreas cancer, liver cancer, kidney cancer, brain cancer, thyroid cancer, ovarian cancer, sarcoma and melanoma, being more preferably breast cancer, lung cancer or kidney cancer.
  • Another related aspect of the present invention is an anti TMEM45A for use in the treatment of a solid tumor cancer affecting a patient, preferably in combination with another chemo therapeutic drug (such as Taxol or etoposide) .
  • another chemo therapeutic drug such as Taxol or etoposide
  • TMEM45A silencing on the protective effect of hypoxia on paclitaxel-induced apoptosis.
  • TMEM45A siRNA siRNA; SEQ. ID. O: 4-6
  • RISC-free control siRNA RF
  • 50nM, 24h MDA-MB-231 cells were incubated under normoxic (N) or hypoxic (H) conditions with or without paclitaxel (tax, 50 ⁇ ) or epirubicin (epi, ⁇ ) for 16 hours.
  • caspase 3 activity was assayed by measuring free AFC released from the cleavage of the caspase 3 specific substrate Ac-DEVD-AFC.
  • TMEM45A for instance NCBI ref seq: NM_018004; SEQ.ID.NO:l
  • NM_018004 for instance NCBI ref seq: NM_018004; SEQ.ID.NO:l
  • TMEM45A for instance NCBI ref seq: NM_018004; SEQ.ID.NO:l
  • TMEM45A gene overexpression was shown to be triggered by hypoxia but can be reduced (in this context) by several drugs, such as anthracyclins (and also mitomycin C or camptothecin) .
  • TMEM45A gives a clue on how a (human) patient suffering of cancer will react to treatments such as to chemotherapeutic drugs (including Taxol or etoposide) .
  • chemotherapeutic such as Taxol or etoposide
  • a first aspect of the present invention is a
  • (diagnostic) method for predicting the response of a (human) patient suffering of a cancer to a chemotherapy treatment such as Paclitaxel (Taxol) or etoposide
  • a chemotherapy treatment such as Paclitaxel (Taxol) or etoposide
  • TMEM45A gene and/or of other genes from Table 1
  • the cancer (to be analyzed in the methods of the present invention) is a solid tumor cancer.
  • the sample (to be analyzed in the methods of the present invention) comprising (consisting essentially of, or consisting of) cancer cells is a tumor sample (e.g. a biopsy) obtained from this solid tumor cancer.
  • solid tumor cancer refers to as a cancer selected from the group consisting of breast cancer, lung cancer, head and neck cancer, colon cancer, pancreas cancer, liver cancer, kidney cancer, brain cancer, thyroid cancer, ovarian cancer, sarcoma and melanoma, being preferably breast cancer, lung cancer, head and neck cancer or kidney cancer .
  • a related aspect of the present invention is a method for monitoring the response of a (human) patient suffering of cancer to a chemotherapy treatment (such as Paclitaxel (Taxol) or etoposide) of this cancer, which comprises the step of measuring the expression level of TMEM45A gene (and/or of other genes from Table 1) in a sample comprising (consisting essentially of, or consisting of) cancer cells.
  • a chemotherapy treatment such as Paclitaxel (Taxol) or etoposide
  • Another related aspect of the present invention is a method for prognosticating the outcome of a cancer in a (human) patient, which comprises the step of measuring the expression level of TMEM45A gene (and/or of other genes from Table 1) in a sample comprising (consisting essentially of, or consisting of) cancer cells.
  • the methods of the present invention further comprise the step of measuring the (relative; e.g. after normalization with housekeeping gene (s) ) expression level of TMEM45A (and/or of other genes from Table 1) in a non-cancer sample consisting of the original and/or native non-cancer cells.
  • these methods further comprise the step of comparing the expression level in the (cells of) the cancer sample and in the (cells of) the non cancer sample, preferably wherein this non cancer sample is obtained from the (same) patient suffering of cancer (for instance a normal breast tissue obtained from the same patient suffering from breast cancer) .
  • TMEM45A protein encoded by TMEM45A gene is quantified (possibly both truncated TMEM45A protein and/or alternatively spliced mRNA and full-length protein and/or mRNA is/are quantified).
  • the expression level of TMEM45A (and/or of other genes from Table 1), when considered as high, represents a worse prognosis and/or a need to select (or to further add) another treatment (including a treatment to inhibit TMEM45A over-expression) and/or a need to avoid (standard) chemotherapy (especially based on taxol or on etoposide) .
  • TMEM45A (and/or of other genes from Table 1) is depicted as a ratio of TMEM45A (and/or of other genes from Table 1) expression in the cancer sample, versus in the normal tissue.
  • a high expression level corresponds to an overexpression in the cancer (tumor) sample of at least 2-fold, preferably at least 3- fold or even 10-fold higher than in the non-cancer sample (but possibly not more than 500-fold or not more than 100- fold) .
  • a related aspect is a diagnostic kit comprising tools for measuring the expression of TMEM45A (and/or of other genes from Table 1) gene.
  • the preferred tools for measuring the expression of TMEM45A gene are for measuring TMEM45A mRNA content, such as primers and probes specifically recognizing parts of the corresponding TMEM45A cDNA (possibly tools for quantifying full-length cDNA and/or tools for quantifying a part (e.g. closer to 5' -end and/or closer to 3' -end) of this cDNA) .
  • TMEM45A gene Alternatively tools for measuring the expression of TMEM45A gene are specific antibodies directed against the protein encoded by this TMEM45A gene (or mRNA) , and/or parts thereof (such as antibodies specifically recognizing epitope (s) close (r) to N-terminal end, and/or epitope (s) close (r) to C-terminal end).
  • the kit of the present invention comprises tools for measuring expression of a (1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or even all the) gene from Table 1, more preferably SPAG4 (possibly in addition to at least another gene of this table) .
  • the kit of the present invention comprises tools for measuring the expression level of less than 100 (different) genes.
  • the kit of the present invention consists (essentially) of tools for measuring the expression level of TMEM45A gene (possibly in addition of tools for measuring the expression of a gene from Table 1 ) .
  • the term "consists essentially of” refers to the presence of tools for measuring the expression level of TMEM45A gene, and also of tools for measuring the expression level of up to a few other genes, such as control genes and/or one of several genes of Table 1.
  • the present invention also relates to the use of this kit for prognosticating the outcome of a cancer or for predicting the response to a chemotherapy treatment of a cancer and/or for monitoring the response to a chemotherapy treatment of a cancer.
  • Another related aspect of the present invention is chemotherapy (such as Paclitaxel or etoposide) for use (or for the manufacture of a medicament for the treatment of) in a patient suffering of a cancer, wherein TMEM45A expression (and/or of other genes from Table 1) in a cancer sample is less than 2-fold higher than in original and/or native non-cancer sample.
  • chemotherapy such as Paclitaxel or etoposide
  • TMEM45A expression and/or of other genes from Table 1
  • Another related aspect of the present invention is an anti TMEM45A (a drug and/or a compound that directly or indirectly inhibits TMEM45A overexpression and/or that reduces TMEM45A amount) for use in the treatment of a solid tumor cancer affecting a (human) patient (or for the manufacture of a medicament for the treatment of a solid tumor cancer), preferably in combination with a (another) chemotherapeutic drug such as hypoxia-inducing drugs and/or taxol and/or etoposide, and preferably in patients having high TMEM45A level (in their cancer cells) .
  • a chemotherapeutic drug such as hypoxia-inducing drugs and/or taxol and/or etoposide
  • MDA-MB-231 breast cancer cells were incubated with or without paclitaxel or epirubicin under normoxia or hypoxia, and caspase 3 activity and cell death, evidenced by LDH release, were assessed.
  • Paclitaxel and epirubicin did trigger apoptosis as well as cell death as shown by an about 2-fold increase in caspase 3 activity and LDH release in normoxia.
  • hypoxia inhibited the paclitaxel- induced increase in caspase 3 activity and LDH release (return to the baseline) .
  • DNA fragmentation and nuclear fragmentation were also assessed. For the latter, the cells were fixed and nuclei were labelled with fluorescent probe DAPI and observed with fluorescent microscopy. An increase in DNA fragmentation was observed in the presence of paclitaxel under normoxia, which was significantly decreased by hypoxia. Moreover, fragmented nuclei were observed in cells exposed to paclitaxel under normoxia but neither in cells exposed to paclitaxel under hypoxia nor in cells that were not incubated with paclitaxel.
  • Unsupervised hierarchical clustering was performed without any gene selection in order to group the conditions on the basis of their similarity measured over all probe sets on the array. Unsupervised cluster analysis using centered correlation and average linkage showed that control cells were well separated from drug-treated cells.
  • hypoxia was separated from normoxia while it was not the case for epirubicin- treated cells.
  • the inventors then compared differences and similarities in gene expression modifications in these conditions and genes were sorted to select only those with a high difference in expression between cells exposed to paclitaxel in normoxia ("N tax”) and cells exposed to paclitaxel in hypoxia (“H tax”), which could therefore be involved in the hypoxia-induced protection against paclitaxel-induced apoptosis.
  • the probe sets were ranked in ascending order of the p values of their differential expression between "N tax” and "H tax", and only highly significant ones with a p value lower than 0.005 were selected. A second round of selection of probe sets was then performed by keeping only those with a minimum fold change of at least 4 times between these 2 conditions.
  • Table 1 shows the 27 genes (from 31 probe sets) selected on the basis of their p value and fold change between "N tax” and "H tax”. [0073] Of note is transmembrane protein 45A
  • TMEM45A which expression was increased up to 16 times between these two conditions and was increased under hypoxic condition with or without paclitaxel but not in the presence of epirubicin.
  • TMEM45A is involved in the hypoxia-induced protection against paclitaxel-induced apoptosis
  • transcriptome data obtained for TMEM45A was then performed using single SYBR Green quantitative real time PCR assays for TMEM45A. Good correlation between relative transcript abundance data obtained by Affymetrix arrays and by real time RT-PCR was observed.
  • siRNA directed against TMEM45A A concentration of 50nM of siRNA was high enough to specifically inhibit the expression of TMEM45A while the RISC-Free negative control siRNA had no effect.
  • TMEM45A is also involved in the hypoxia- induced protection of HepG2 cells against etoposide-induced apoptosis .
  • the inventors further used another experimental model: HepG2 hepatocellular carcinoma cells exposed to etoposide.
  • the inventors wanted to determine if TMEM45A could also be involved in the protection of HepG2 cells against apoptosis induced by etoposide under hypoxia.
  • TMEM45A mRNA expression was shown to be increased by 5.5 fold in HepG2 cells incubated in the presence or in the absence of etoposide incubated under hypoxia. This increase correlated with the protective effect of hypoxia against etoposide-induced apoptosis. The inventors then determined that a concentration of 50 nM of TMEM45A siRNA was high enough to specifically inhibit TMEM45A mRNA expression while the RISC-Free control siRNA had no effect.
  • Caspase 3 activity was then assessed in cells transfected with TMEM45A or negative control siRNA before being incubated under normoxia or hypoxia in the presence or in the absence of etoposide. Caspase 3 activity was significantly increased for TMEM45A siRNA transfected HepG2 cells incubated with etoposide under hypoxia. No modification was observed in control cells and in cells incubated with etoposide under normoxia.
  • the caspase 3 activity measured for anti-TMEM45A siRNA transfected cells incubated under hypoxia with etoposide reached similar level than the activity measured for non transfected cells incubated in normoxia with etoposide, indicating that the protection was completely reversed when TMEM45A was silenced .
  • TMEM45A overexpression is associated with a high risk of breast cancer recurrence
  • the inventors then performed survival analysis using the Kaplan-Meier method on data from a study involving 286 patients with primary breast cancer and available clinical parameters. These patients were allocated to one of two subgroups of 143 patients stratified by TMEM45A expression. Kaplan-Meier graph compares the disease-free survival for groups of patients high and low TMEM45A expression (Fig. 2) . The results show that patients whose tumors had high TMEM45A expression had a significantly lower relapse-free survival than those whose tumors had a low TMEM45A expression (P ⁇ 0.01).
  • TMEM45A expression was 7-fold higher in these cancer patients.
  • TMEM45A expression was 2.5-fold higher in these cancer patients.
  • the type 1 tumors (which, due to its histological features, is associated to a worse prognosis) had a 3.5 fold induction of TMEM54A, while the type 2 tumors (associated to a better prognosis) had no induction of TMEM54A expression (same level as in healthy tissue) .
  • the inventors then treated patient suffering from several cancers with chemotherapeutic drugs such as taxol or etoposide and measured better relapse-free response in patients having (and keeping) low TMEM45A expression level in tumor sample.
  • chemotherapeutic drugs such as taxol or etoposide
  • TMEM45A overexpression in patients .

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Abstract

A method for prognosticating the outcome of a cancer, for predicting the response to a chemotherapy treatment of a cancer or for monitoring the response to a chemotherapy treatment of a cancer, comprising the step of measuring the expression level of TMEM45A gene in a sample

Description

METHOD AND KIT FOR PREDICTING OR MONITORING THE RESPONSE OF A CANCER PATIENT TO|CHEMOTHERAPY, BASED ON MEASURING THE EXPRESSION LEVEL OF TMEM45A GENE.
Background of the invention
[0001] The present invention is in the field of cancer diagnostic in relation to TMEM45A expression, and of associated treatments. State of the Art
[0002] The development of therapy resistance continues to be a major problem in the treatment of patients with cancer. Insights into treatment failure have been very recently identified as one of the major issues in cancer research.
[0003] The overexpression of efflux pump, such as the P-glycoprotein encoded by the MDR1 gene or proteins from ABC (ATP-binding cassette) transporter family, which expulses the chemotherapeutic drug out of the tumor cells represents a paradigm of therapy resistance.
[0004] It is thought that hypoxia, according to its severity, can either promote apoptosis and cell death or contrariwise induce cell growth and survival by provoking an adaptive response. For instance, tumor hypoxia has been associated with resistance to chemotherapy and radiotherapy, with tumor progression, aggressiveness and metastasis, and therefore with an increased probability of tumor recurrence. [0005] The function of TMEM45A protein is almost unknown, and nothing is known about its cellular localization .
[0006] TMEM45A was found upregulated in hypoxia in umbilical cord blood CD133+ cells.
[0007] Lee et al . , Cancer Res., 2012, July, 2, has disclosed in a mice model that the suppression of expression of several genes, including TMEM45A, increased the progression of xenografts to invasive cancer.
Summary of the invention
[0008] A first aspect of the present invention is a method for predicting the response of a human patient (suffering of a cancer) to a chemotherapy treatment (such as Taxol or etoposide) against this cancer, (this method) comprising the step of measuring the expression level of TMEM45A gene in a sample (e.g. a tumor sample) consisting essentially of cancer cells obtained from this human patient suffering of cancer.
[0009] A related aspect of the present invention is a method for monitoring the response of a human patient (suffering of cancer) to a chemotherapy (such as Taxol or etoposide) treatment against this cancer, (this method) comprising the step of measuring the expression level of TMEM45A gene in a sample (e.g. a tumor sample) consisting essentially of cancer cells obtained from this human patient suffering of cancer.
[0010] Another related aspect of the present invention is a method for prognosticating the outcome of a cancer in a human patient comprising the step of measuring the expression level of TMEM45A gene in a sample (e.g. a tumor sample) consisting essentially of cancer cells obtained from this human patient suffering of cancer. [0011] Preferably in these methods the cancer is a solid tumor cancer, more preferably selected from the group consisting of breast cancer, lung cancer, colon cancer, head and neck cancer, pancreas cancer, liver cancer, kidney cancer, brain cancer, thyroid cancer, ovarian cancer, sarcoma and melanoma, being more still preferably breast cancer, head and neck cancer, lung cancer or kidney cancer.
[0012] Preferably these methods further comprise the step of measuring the expression level of TMEM45A gene in a non-cancer sample consisting of the original and/or native non-cancer cells and possibly the step of comparing the expression level in the cancer cells and in the non cancer cells, possibly wherein this non cancer sample is obtained from the human patient suffering of cancer.
[0013] Advantageously, in the methods of the invention, a high expression level of TMEM45A gene corresponds to a ratio of TMEM45A gene expression in the cancer sample being of at least 2-fold, preferably at least 3-fold or even at least 10-fold higher than in the non- cancer sample.
[0014] Such a high expression level represents a worse prognosis and/or a resistance towards chemotherapeutic agents (such as Taxol or etoposide) .
[0015] Preferably in these methods the chemotherapy treatment is Paclitaxel (Taxol) or etoposide.
[0016] Preferably these methods further comprise the step of measuring the expression level of at least another (1, 2, 3, 4, 5 or even all the) gene(s) selected from Table 1, preferably at least SPAG4 gene, in the sample consisting essentially of cancer cells, and possibly also in the sample consisting of the original and/or native non-cancer cells . [0017] Another related aspect of the present invention is a diagnostic kit comprising tools for measuring the expression of TMEM45A gene.
[0018] Advantageously this kit comprises tools for measuring the expression level of less than 100 other genes than TMEM45A gene.
[0019] Preferably this kit further comprises tools for measuring the expression level of at least another (1, 2, 3, 4, 5 or even all the) gene(s) selected from Table 1, preferably at least SPAG4 gene.
[0020] Possibly this kit consists essentially of tools for measuring the expression of TMEM45A gene (and possibly of gene(s) from Table 1) .
[0021] Another related aspect of the present invention is the use of the kit of the present invention for prognosticating the outcome of a cancer in a human patient, or for predicting the response to a chemotherapy treatment of a cancer in a human patient, and/or for monitoring the response to a chemotherapy treatment of a cancer in a human patient.
[0022] This use is preferably applied on (genes and/or mRNA and/or proteins isolated from) a solid tumor cancer, preferably selected from the group consisting of breast cancer, lung cancer, colon cancer, pancreas cancer, head and neck cancer, liver cancer, kidney cancer, brain cancer, thyroid cancer, ovarian cancer, sarcoma and melanoma, being more preferably breast cancer, lung cancer, head and neck cancer or kidney cancer.
[0023] Another related aspect of the present invention is chemotherapy (such as Taxol or etoposide) for use in a human patient suffering of a cancer, wherein TMEM45A gene expression in a cancer sample is less than 2- fold higher than in original and/or native non-cancer sample . [0024] The preferred chemotherapy treatment are selected from the group consisting of Paclitaxel (taxol) and etoposide.
[0025] Alternatively, anthracyclines (and also mitomycin C or camptothecin) can be used in patients having a high expression (a ratio of expression of more than 2- fold, preferably more than 3-fold) level of TMEM45A.
[0026] These chemotherapy treatments are preferably used for the treatment of solid tumor cancers, preferably selected from the group consisting of breast cancer, lung cancer, colon cancer, pancreas cancer, liver cancer, kidney cancer, brain cancer, thyroid cancer, ovarian cancer, sarcoma and melanoma, being more preferably breast cancer, lung cancer or kidney cancer.
[0027] Another related aspect of the present invention is an anti TMEM45A for use in the treatment of a solid tumor cancer affecting a patient, preferably in combination with another chemo therapeut ic drug (such as Taxol or etoposide) .
Brief description of the figures and tables
Table 1
[0028] Gene expression profiling in MDA-MB-231 cells incubated with or without paclitaxel (tax) or epirubicin (epi) under normoxic (N) or hypoxic (H) conditions. Cells were incubated in the different conditions for 16 hours before RNA extraction, target preparation, hybridization to Affymetrix HG-U133 Plus 2.0 arrays, washing and array signal acquisition. Each value of the fold induction columns is the average of three ratio values calculated from three independent experiments. These 27 candidate genes were selected on the basis of their p value (p<0.005) and fold change (at least 4 times) between "N tax" and "H tax" . Figure 1
[0029] Effect of TMEM45A silencing on the protective effect of hypoxia on paclitaxel-induced apoptosis. 8 h post transfection with TMEM45A siRNA (siRNA; SEQ. ID. O: 4-6) or RISC-free control siRNA (RF) (50nM, 24h) , MDA-MB-231 cells were incubated under normoxic (N) or hypoxic (H) conditions with or without paclitaxel (tax, 50μΜ) or epirubicin (epi, ΙΟμΜ) for 16 hours. After transfection and incubation, caspase 3 activity was assayed by measuring free AFC released from the cleavage of the caspase 3 specific substrate Ac-DEVD-AFC. Results are expressed in fluorescence intensity, as mean ± 1 SD (n=3) . Statistical analyses were determined independently for the 3 subgroups without siRNA, with TMEM45A siRNA (siRNA) and with RISC- free control siRNA (RF) ; N.S. = non significantly different from control (N, N siRNA or N RF) , ** = significantly different from control (p<0.01), *** = significantly different from control (p<0.001) ; N.S. <u = no significant difference between N epi and H epi, ### = significant difference between N tax and H tax (p<0.001), # = significant difference between N epi and H epi (p<0.05) . N.S. = no significant difference between (2> N tax and N tax RF or (3) H tax and H tax RF, ··· = significant difference between (u N tax and N tax siRNA or (2> H tax and H tax siRNA (p<0.001) .
Figure 2
[0030] Kaplan-Meier probability of relapse-free survival for 286 patients with lymph-node-negative breast cancer allocated to one of two subgroups stratified by TMEM45A expression. Low TMEM45A expression represents a better outcome. Detailed description of the invention
[0031] Despite new discoveries in the molecular alterations that lead to tumorigenesis as well new treatments and therapeutic strategies developed against cancer, primary treatment failure and relapse after treatment are common and death due to cancer remains too frequent. The development of chemotherapy resistance still brings significant problems to patients and to physicians who rely on conventional cytotoxic agents for the treatment of malignant disease.
[0032] The inventors have found that TMEM45A (for instance NCBI ref seq: NM_018004; SEQ.ID.NO:l) expression correlates with a worse prognostic for (human) patients suffering of a cancer.
[0033] Moreover, overexpression of this TMEM45A gene was shown to be triggered by hypoxia but can be reduced (in this context) by several drugs, such as anthracyclins (and also mitomycin C or camptothecin) .
[0034] Therefore, the expression level of TMEM45A gives a clue on how a (human) patient suffering of cancer will react to treatments such as to chemotherapeutic drugs (including Taxol or etoposide) .
[0035] In addition, the monitoring of the expression level of TMEM45A during treatment gives clues as to when a (human) patient will no longer benefit from the ongoing treatment (e.g. chemotherapeutic, such as Taxol or etoposide) , meaning a need to shift to another treatment and/or to inhibit in the (human) patient TMEM45A over- expression .
[0036] A first aspect of the present invention is a
(diagnostic) method for predicting the response of a (human) patient suffering of a cancer to a chemotherapy treatment (such as Paclitaxel (Taxol) or etoposide) against this cancer, which comprises the step of measuring the expression level of TMEM45A gene (and/or of other genes from Table 1) in a sample comprising (consisting essentially of, or consisting of) cancer cells.
[0037] Preferably, the cancer (to be analyzed in the methods of the present invention) is a solid tumor cancer.
[0038] Preferably, the sample (to be analyzed in the methods of the present invention) comprising (consisting essentially of, or consisting of) cancer cells is a tumor sample (e.g. a biopsy) obtained from this solid tumor cancer.
[0039] In the context of the present invention, the term "solid tumor cancer" refers to as a cancer selected from the group consisting of breast cancer, lung cancer, head and neck cancer, colon cancer, pancreas cancer, liver cancer, kidney cancer, brain cancer, thyroid cancer, ovarian cancer, sarcoma and melanoma, being preferably breast cancer, lung cancer, head and neck cancer or kidney cancer .
[0040] A related aspect of the present invention is a method for monitoring the response of a (human) patient suffering of cancer to a chemotherapy treatment (such as Paclitaxel (Taxol) or etoposide) of this cancer, which comprises the step of measuring the expression level of TMEM45A gene (and/or of other genes from Table 1) in a sample comprising (consisting essentially of, or consisting of) cancer cells.
[0041] Another related aspect of the present invention is a method for prognosticating the outcome of a cancer in a (human) patient, which comprises the step of measuring the expression level of TMEM45A gene (and/or of other genes from Table 1) in a sample comprising (consisting essentially of, or consisting of) cancer cells.
[0042] Preferably, the methods of the present invention further comprise the step of measuring the (relative; e.g. after normalization with housekeeping gene (s) ) expression level of TMEM45A (and/or of other genes from Table 1) in a non-cancer sample consisting of the original and/or native non-cancer cells. Preferably, these methods further comprise the step of comparing the expression level in the (cells of) the cancer sample and in the (cells of) the non cancer sample, preferably wherein this non cancer sample is obtained from the (same) patient suffering of cancer (for instance a normal breast tissue obtained from the same patient suffering from breast cancer) .
[0043] Preferably, the expression level of TMEM45A
(and/or of other genes from Table 1) is measured upon TMEM45A mRNA quantification. Alternatively, TMEM45A protein encoded by TMEM45A gene is quantified (possibly both truncated TMEM45A protein and/or alternatively spliced mRNA and full-length protein and/or mRNA is/are quantified).
[0044] Possibly, in the methods of the present invention the expression level of TMEM45A (and/or of other genes from Table 1), when considered as high, represents a worse prognosis and/or a need to select (or to further add) another treatment (including a treatment to inhibit TMEM45A over-expression) and/or a need to avoid (standard) chemotherapy (especially based on taxol or on etoposide) .
[0045] Preferably, the expression level of TMEM45A
(and/or of other genes from Table 1) is depicted as a ratio of TMEM45A (and/or of other genes from Table 1) expression in the cancer sample, versus in the normal tissue.
[0046] In the present invention, a high expression level corresponds to an overexpression in the cancer (tumor) sample of at least 2-fold, preferably at least 3- fold or even 10-fold higher than in the non-cancer sample (but possibly not more than 500-fold or not more than 100- fold) . [0047] A related aspect is a diagnostic kit comprising tools for measuring the expression of TMEM45A (and/or of other genes from Table 1) gene.
[0048] The preferred tools for measuring the expression of TMEM45A gene are for measuring TMEM45A mRNA content, such as primers and probes specifically recognizing parts of the corresponding TMEM45A cDNA (possibly tools for quantifying full-length cDNA and/or tools for quantifying a part (e.g. closer to 5' -end and/or closer to 3' -end) of this cDNA) .
[0049] Alternatively tools for measuring the expression of TMEM45A gene are specific antibodies directed against the protein encoded by this TMEM45A gene (or mRNA) , and/or parts thereof (such as antibodies specifically recognizing epitope (s) close (r) to N-terminal end, and/or epitope (s) close (r) to C-terminal end).
[0050] Preferably, the kit of the present invention comprises tools for measuring expression of a (1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or even all the) gene from Table 1, more preferably SPAG4 (possibly in addition to at least another gene of this table) .
[0051] Preferably, the kit of the present invention comprises tools for measuring the expression level of less than 100 (different) genes.
[0052] Alternatively, or in addition, the kit of the present invention consists (essentially) of tools for measuring the expression level of TMEM45A gene (possibly in addition of tools for measuring the expression of a gene from Table 1 ) .
[0053] In the context of the present invention, the term "consists essentially of" refers to the presence of tools for measuring the expression level of TMEM45A gene, and also of tools for measuring the expression level of up to a few other genes, such as control genes and/or one of several genes of Table 1.
[0054] The present invention also relates to the use of this kit for prognosticating the outcome of a cancer or for predicting the response to a chemotherapy treatment of a cancer and/or for monitoring the response to a chemotherapy treatment of a cancer.
[0055] Another related aspect of the present invention is chemotherapy (such as Paclitaxel or etoposide) for use (or for the manufacture of a medicament for the treatment of) in a patient suffering of a cancer, wherein TMEM45A expression (and/or of other genes from Table 1) in a cancer sample is less than 2-fold higher than in original and/or native non-cancer sample.
[0056] Another related aspect of the present invention is an anti TMEM45A (a drug and/or a compound that directly or indirectly inhibits TMEM45A overexpression and/or that reduces TMEM45A amount) for use in the treatment of a solid tumor cancer affecting a (human) patient (or for the manufacture of a medicament for the treatment of a solid tumor cancer), preferably in combination with a (another) chemotherapeutic drug such as hypoxia-inducing drugs and/or taxol and/or etoposide, and preferably in patients having high TMEM45A level (in their cancer cells) .
Examples Example 1
[0057] Hypoxia protects MDA-MB-231 cells against paclitaxel-induced apoptosis
[0058] MDA-MB-231 breast cancer cells were incubated with or without paclitaxel or epirubicin under normoxia or hypoxia, and caspase 3 activity and cell death, evidenced by LDH release, were assessed.
[0059] Hypoxia per se did not induce apoptosis or cell death since no increase in caspase 3 activity or in LDH release were observed.
[0060] Paclitaxel and epirubicin did trigger apoptosis as well as cell death as shown by an about 2-fold increase in caspase 3 activity and LDH release in normoxia.
[0061] Hypoxia did not modify the epirubicin-induced apoptosis and cell death.
[0062] However, hypoxia inhibited the paclitaxel- induced increase in caspase 3 activity and LDH release (return to the baseline) .
[0063] DNA fragmentation and nuclear fragmentation were also assessed. For the latter, the cells were fixed and nuclei were labelled with fluorescent probe DAPI and observed with fluorescent microscopy. An increase in DNA fragmentation was observed in the presence of paclitaxel under normoxia, which was significantly decreased by hypoxia. Moreover, fragmented nuclei were observed in cells exposed to paclitaxel under normoxia but neither in cells exposed to paclitaxel under hypoxia nor in cells that were not incubated with paclitaxel.
[0064] All together, these data demonstrate that hypoxia is able to protect MDA-MB-231 cells against the chemotherapeutic agent paclitaxel-induced apoptosis.
Example 2
[0065] Hypoxia and paclitaxel or epirubicin induce changes in gene expression
[0066] In order to identify the mechanism(s) responsible for the hypoxia-induced protection, whole transcriptome studies were performed using RNA isolated for control cells and cells incubated in the presence of taxol or epirubicin, both under normoxia and hypoxia. Experimental triplicates were analyzed for each experimental condition.
[0067] Unsupervised hierarchical clustering was performed without any gene selection in order to group the conditions on the basis of their similarity measured over all probe sets on the array. Unsupervised cluster analysis using centered correlation and average linkage showed that control cells were well separated from drug-treated cells.
[0068] Moreover, for control cells and cells incubated in the presence of taxol, hypoxia was separated from normoxia while it was not the case for epirubicin- treated cells.
[0069] These results are in good accordance with the protection of the drug-induced apoptosis brought by hypoxia for paclitaxel but not for epirubicin.
[0070] The inventors then compared differences and similarities in gene expression modifications in these conditions and genes were sorted to select only those with a high difference in expression between cells exposed to paclitaxel in normoxia ("N tax") and cells exposed to paclitaxel in hypoxia ("H tax"), which could therefore be involved in the hypoxia-induced protection against paclitaxel-induced apoptosis.
[0071] The probe sets were ranked in ascending order of the p values of their differential expression between "N tax" and "H tax", and only highly significant ones with a p value lower than 0.005 were selected. A second round of selection of probe sets was then performed by keeping only those with a minimum fold change of at least 4 times between these 2 conditions.
[0072] Table 1 shows the 27 genes (from 31 probe sets) selected on the basis of their p value and fold change between "N tax" and "H tax". [0073] Of note is transmembrane protein 45A
(TMEM45A) which expression was increased up to 16 times between these two conditions and was increased under hypoxic condition with or without paclitaxel but not in the presence of epirubicin.
Example 3
[0074] TMEM45A is involved in the hypoxia-induced protection against paclitaxel-induced apoptosis
Validation of transcriptome data obtained for TMEM45A was then performed using single SYBR Green quantitative real time PCR assays for TMEM45A. Good correlation between relative transcript abundance data obtained by Affymetrix arrays and by real time RT-PCR was observed.
[0075] TMEM45A expression was invalidated in MDA-MB-
231 using siRNA directed against TMEM45A. A concentration of 50nM of siRNA was high enough to specifically inhibit the expression of TMEM45A while the RISC-Free negative control siRNA had no effect.
[0076] Cells were then transfected with anti-TMEM45A or control siRNA before being incubated under normoxia or hypoxia in the presence of one or the other chemotherapeutic agent. Caspase 3 activity was then assessed. If TMEM45A plays an anti-apoptot ic role, an increase in the paclitaxel-induced caspase 3 activity is expected when inhibited by specific siRNA. Figure 1 shows that caspase 3 activity was significantly increased for TMEM45A siRNA transfected cells incubated with paclitaxel or epirubicin, under normoxia as well as under hypoxia. The caspase 3 activity measured for TMEM45A siRNA transfected cells incubated with paclitaxel under hypoxia reached a level much higher than the activity measured for non transfected cells incubated with paclitaxel in normoxia, indicating that the protection was reversed in this case. No modification was observed in cells transfected with the negative control siRNA.
[0077] The inventors then confirmed these observations by determining the effect of TMEM45A silencing on paclitaxel induced DNA fragmentation. The negative control siRNA did not influence DNA fragmentation, whereas TMEM45A siRNA transfection induced a strong and significant increase in DNA fragmentation for cells incubated in the presence of paclitaxel under normoxia or hypoxia compared to non transfected cells incubated in the same conditions. These results clearly demonstrate for the first time an implication of TMEM45A in the hypoxia-induced protection against the apoptosis induced by paclitaxel. Example 4
[0078] TMEM45A is also involved in the hypoxia- induced protection of HepG2 cells against etoposide-induced apoptosis .
The inventors further used another experimental model: HepG2 hepatocellular carcinoma cells exposed to etoposide. The inventors wanted to determine if TMEM45A could also be involved in the protection of HepG2 cells against apoptosis induced by etoposide under hypoxia.
[0079] TMEM45A mRNA expression was shown to be increased by 5.5 fold in HepG2 cells incubated in the presence or in the absence of etoposide incubated under hypoxia. This increase correlated with the protective effect of hypoxia against etoposide-induced apoptosis. The inventors then determined that a concentration of 50 nM of TMEM45A siRNA was high enough to specifically inhibit TMEM45A mRNA expression while the RISC-Free control siRNA had no effect.
[0080] Caspase 3 activity was then assessed in cells transfected with TMEM45A or negative control siRNA before being incubated under normoxia or hypoxia in the presence or in the absence of etoposide. Caspase 3 activity was significantly increased for TMEM45A siRNA transfected HepG2 cells incubated with etoposide under hypoxia. No modification was observed in control cells and in cells incubated with etoposide under normoxia. The caspase 3 activity measured for anti-TMEM45A siRNA transfected cells incubated under hypoxia with etoposide reached similar level than the activity measured for non transfected cells incubated in normoxia with etoposide, indicating that the protection was completely reversed when TMEM45A was silenced .
Example 5
[0081] TMEM45A overexpression is associated with a high risk of breast cancer recurrence
The inventors then performed survival analysis using the Kaplan-Meier method on data from a study involving 286 patients with primary breast cancer and available clinical parameters. These patients were allocated to one of two subgroups of 143 patients stratified by TMEM45A expression. Kaplan-Meier graph compares the disease-free survival for groups of patients high and low TMEM45A expression (Fig. 2) . The results show that patients whose tumors had high TMEM45A expression had a significantly lower relapse-free survival than those whose tumors had a low TMEM45A expression (P < 0.01).
Example 6
[0082] TMEM45A overexpression in several cancers
[0083] The inventors then measured TMEM45A expression in kidney tissue obtained from healthy human donors and compared the value with TMEM45A expression measured on a tumor obtained from human patients suffering from kidney cancer. TMEM45A expression was 7-fold higher in these cancer patients.
[0084] The inventors then measured TMEM45A expression in lung tissue obtained from healthy human donors and compared the value with TMEM45A expression measured on a tumor obtained from human patients suffering from lung cancer. TMEM45A expression was 2.5-fold higher in these cancer patients. Interestingly, when further characterizing the tumors by morphological tests, the type 1 tumors (which, due to its histological features, is associated to a worse prognosis) had a 3.5 fold induction of TMEM54A, while the type 2 tumors (associated to a better prognosis) had no induction of TMEM54A expression (same level as in healthy tissue) .
[0085] Similar results were also obtained for several brain cancers, including glioblastoma.
[0086] The inventors then treated patient suffering from several cancers with chemotherapeutic drugs such as taxol or etoposide and measured better relapse-free response in patients having (and keeping) low TMEM45A expression level in tumor sample.
Example 7
[0087] Inhibition of TMEM45A overexpression in cancer treatment
[0088] The inventors have applied several inhibitors
(such as hypoxia-inducible factor 1, and chemotherapeutic drugs) in order to block TMEM45A overexpression in patients .
[0089] Overall, the inventors have noticed a better outcome in these treated patients.
[0090] The inventors therefore conclude that such treatments are valuable, especially in patients having high TMEM45A level and/or in combination with other chemotherapeutic drugs such as Taxol or etoposide.

Claims

1. A method for predicting the response of a human patient suffering of a cancer to a chemotherapy treatment against the said cancer and/or for monitoring the response of a human patient suffering of cancer to a chemotherapy treatment against the said cancer or for prognosticating the outcome of a cancer in a human patient, comprising the steps of
- measuring the expression level of TMEM45A gene in a sample consisting essentially of cancer cells obtained from the said human patient suffering of cancer and - measuring the expression level of TMEM45A gene in a non-cancer sample consisting of the original and/or native non-cancer cells.
2. The method of claim 1, wherein the cancer is a solid tumor cancer, preferably selected from the group consisting of breast cancer, lung cancer, colon cancer, head and neck cancer, pancreas cancer, liver cancer, kidney cancer, brain cancer, thyroid cancer, ovarian cancer, sarcoma and melanoma, being more preferably breast cancer, head and neck cancer, lung cancer or kidney cancer.
3. The method of claim 1 or 2, further comprising the step of comparing the expression level of TMEM45A in the cancer sample and in the non cancer sample, preferably wherein the said non cancer sample is obtained from the human patient suffering of cancer.
4. The method of claim 3, wherein high expression level of TMEM45A gene corresponds to a ratio of TMEM45A gene expression in the cancer sample being of at least 2-fold, preferably at least 3-fold or even at least 10-fold higher than in the non-cancer sample.
5. The method according to any of the preceding claims wherein the chemotherapy treatment is Paclitaxel (taxol) or etoposide.
6. The method according to any of the preceding claims further comprising the step of measuring the expression level of at least another (1, 2, 3, 4, 5 or even all the) gene(s) selected from Table 1, preferably at least SPAG4 gene, in the sample consisting essentially of cancer cells, and possibly also in the sample consisting of the original and/or native non-cancer cells.
7. A diagnostic kit comprising tools for measuring the expression of TMEM45A gene and tools for measuring at least another gene(s) selected from Table 1, preferably at least SPAG4 gene.
8. The kit of claim 7 comprising tools for measuring the expression level of less than 100 other genes than TMEM45A gene.
9. The kit of claim 7 or 8 consisting essentially of tools for measuring the expression of TMEM45A gene and of gene(s) from Table 1.
10. Use of the kit according to any of the preceding claims 7 to 9 for prognosticating the outcome of a cancer in a human patient, or for predicting the response to a chemotherapy treatment of a cancer in a human patient, and/or for monitoring the response to a chemotherapy treatment of a cancer in a human patient.
11. The use of claim 10, wherein the cancer is a solid tumor cancer, preferably selected from the group consisting of breast cancer, lung cancer, colon cancer, pancreas cancer, head and neck cancer, liver cancer, kidney cancer, brain cancer, thyroid cancer, ovarian cancer, sarcoma and melanoma, being more preferably breast cancer, lung cancer, head and neck cancer or kidney cancer.
12. Chemotherapy selected from the group consisting of Paclitaxel (taxol) and etoposide for use in a human patient suffering of a cancer, wherein TMEM45A gene expression in a cancer sample is less than 2-fold higher than in original and/or native non-cancer sample.
13. Anthracyclines for use in a human patient suffering of a cancer, wherein TMEM45A gene expression in a cancer sample is at least 2-fold higher than in original and/or native non-cancer sample.
14. The treatment of claim 13 or 14, wherein the cancer is a solid tumor cancer, preferably selected from the group consisting of breast cancer, lung cancer, colon cancer, pancreas cancer, liver cancer, kidney cancer, brain cancer, thyroid cancer, ovarian cancer, sarcoma and melanoma, being more preferably breast cancer, lung cancer or kidney cancer.
15. Anti TMEM45A for use in the treatment of a solid tumor cancer affecting a patient, preferably in combination with another chemotherapeut ic drug, more preferably selected from the group consisting of Paclitaxel (taxol) and etoposide.
EP13727840.4A 2012-07-12 2013-05-31 Method and kit for predicting or monitoring the response of a cancer patient to chemotherapy, based on measuring the expression level of tmem45a gene. Withdrawn EP2872645A1 (en)

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008077165A1 (en) * 2006-12-22 2008-07-03 Austrian Research Centers Gmbh - Arc Set of tumor markers
US20090239223A1 (en) * 2006-07-13 2009-09-24 Siemens Healthcare Diagnostics Inc. Prediction of Breast Cancer Response to Taxane-Based Chemotherapy

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WO2012022634A1 (en) * 2010-08-16 2012-02-23 Institut National De La Sante Et De La Recherche Medicale (Inserm) Classification, diagnosis and prognosis of multiple myeloma

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20090239223A1 (en) * 2006-07-13 2009-09-24 Siemens Healthcare Diagnostics Inc. Prediction of Breast Cancer Response to Taxane-Based Chemotherapy
WO2008077165A1 (en) * 2006-12-22 2008-07-03 Austrian Research Centers Gmbh - Arc Set of tumor markers

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
ANNE P. G CRIJNS ET AL: "Survival-Related Profile, Pathways, and Transcription Factors in Ovarian Cancer", PLOS MEDICINE, vol. 6, no. 2, 3 February 2009 (2009-02-03), US, pages e1000024, XP055360913, ISSN: 1549-1277, DOI: 10.1371/journal.pmed.1000024 *
See also references of WO2014009055A1 *

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