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WO2019115679A1 - Signature permettant l'évaluation d'un pronostic et d'un régime thérapeutique dans le cancer du foie - Google Patents

Signature permettant l'évaluation d'un pronostic et d'un régime thérapeutique dans le cancer du foie Download PDF

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WO2019115679A1
WO2019115679A1 PCT/EP2018/084719 EP2018084719W WO2019115679A1 WO 2019115679 A1 WO2019115679 A1 WO 2019115679A1 EP 2018084719 W EP2018084719 W EP 2018084719W WO 2019115679 A1 WO2019115679 A1 WO 2019115679A1
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biomarkers
patients
protein
concentration
tumor
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PCT/EP2018/084719
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English (en)
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Carolina Armengol Niell
Marina SIMON COMA
Juan CARRILLO REIXACH
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Fundació Institut D'investigació En Ciències De La Salut Germans Trias I Pujol
Consorcio Centro de Investigación Biomédica en Red, M.P.
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Publication of WO2019115679A1 publication Critical patent/WO2019115679A1/fr

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    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
    • G01N33/574—Immunoassay; Biospecific binding assay; Materials therefor for cancer
    • G01N33/57407—Specifically defined cancers
    • G01N33/57438—Specifically defined cancers of liver, pancreas or kidney
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2800/00—Detection or diagnosis of diseases
    • G01N2800/52—Predicting or monitoring the response to treatment, e.g. for selection of therapy based on assay results in personalised medicine; Prognosis

Definitions

  • the present disclosure generally relates to biomarkers and their use for the prognosis of liver cancer.
  • Liver cancer also known as hepatic cancer and primary hepatic cancer, is a cancer that starts in the liver.
  • the most frequent is the Hepatocellular Carcinoma (HCC) which is the sixth most commonly occurring cancer in the world, the third leading cause of cancer mortality and it is mainly diagnosed in adults with an underlying liver disease.
  • HCC Hepatocellular Carcinoma
  • HB Hepatoblastoma
  • Pediatric HCC (pHCC) is even rarer than HB and is usually diagnosed in older patients and adolescents.
  • the annual incidence of HB is of 1.5 cases/million children under 15 years.
  • HB is typically diagnosed during lactation or in young children (88% of cases occur in children under 5 years).
  • pHCC is the second most common liver tumor in children being most of the cases diagnosed after 10 years of age and it is the main hepatic tumor in adolescents.
  • most cases in children are de novo tumors, not related to liver damage.
  • HCC and HB primary liver cancers
  • prognosis stratification for the above mentioned cancers and consequent treatment options are difficult to predict and they are mainly based to clinical (patient age, general status of the patient, liver function, portal pressure, serum bilirubin and alpha-fetoprotein levels), surgical (tumor resectability, potential candidate for liver transplantation) and tumor (tumor size, tumor hepatic extension, tumor rupture, blood tumor invasion or spread to other places in the body) parameters (Bruix et al, Gastroenterology, 2016; Meyers et al, Lancet Oncology, 2017).
  • the current risk stratification system at diagnosis is based on the Children’s Hepatic Tumors International Collaboration (CHIC) classification.
  • This system is mainly based in the PRETEXT (pre-treatment extent of disease) system and its combination with different clinical parameters such as presence of metastasis, patient age, serum AFP levels, tumor resectability and tumor spreading (i.e. intra-growth blood vessels, multifocality, tumor rupture, contiguous extrahepatic growth, caudate and lymph node involvement, metastasis).
  • the PRETEXT (pre-treatment extent of disease) system designed by the International Childhood Liver Tumor Strategy Group (SIOPEL) is a non-invasive technique commonly used by clinicians, to assess the extent of liver cancer at diagnosis, to determine the time of surgery and to adapt the treatment protocol. This system is based on the division of the liver in four parts and the determination of the number of liver sections that are free of tumor.
  • the PRETEXT system even if reproducible and providing good prognostic value, is mainly based on imaging criteria, making this system dependent upon the technicians and clinicians. There is thus a need for a system, complementary to the current clinical CHIC stratification, based on genetic and molecular features of the liver tumors to improve the patient prognosis prediction.
  • the main finding relating to molecular classification is the identification of two HB subclasses, called C1 and C2, which have been described associated to different prognosis of liver cancer (Cairo-Armengol et al, Cancer Cell, 2008) but the 16-gene signature able to assess these two tumor subclasses is difficult to implement in the clinical setting.
  • the present invention is thus focused to provide a new biomarker, called the 3- protein signature, easy to assess at the Pathology service of any hospital with the intention to improve the treatment, preferably at diagnosis or after surgery, of any patient diagnosed with HB, pHCC or HCC with the final aim to improve quality of life and survival rates of these patients.
  • Fig. 1 Hierarchical cluster analysis of the proteomic data clearly distinguished the two HB molecular prognostic subtypes, C1 and C2.
  • A Representative unsupervised hierarchical clustering (Pearson distance; Linkage method: Complete of protein expression profiles obtained from 277 Two-dimensional differential in-gel electrophoresis (DIGE) spots corresponding to the top 50% highest coefficient of variation (CV) spots of 16 HBs and 8 non-tumor samples.
  • DIGE Two-dimensional differential in-gel electrophoresis
  • CV coefficient of variation spots of 16 HBs and 8 non-tumor samples.
  • B Representative unsupervised hierarchical clustering of protein expression profiles obtained from 390 proteins (50% CV) identified by Label-Free (LF) mass spectrometry analysis of 8 HBs and 4 non-tumor samples.
  • T tumor
  • NT non-tumor (white squares)
  • R experimental replicate.
  • Tumor samples were classified according to the 16-gene signature (Cairo et al., 2008) as C1 and C2 (green and red squares, respectively). Black boxes in the rows above the heat maps indicate (from top to bottom): dead of the disease, metastasis at diagnosis, and non-fetal main epithelial component.
  • Fig. 2 Table of the main deregulated proteins between the two C1 and C2 HB prognostic subclasses as well as C1/NL and/or C2/NL identified by DIGE and/or LF proteomic techniques (p value ⁇ 0.01 , FC ⁇ 2). In blue, proteins selected for Western Blot validation.
  • Fig. 3 Study of the protein expression of the 8 selected prognostic biomarkers by using the Western blot (WB) technique: Identification of the 3 prognostic biomarkers.
  • A Protein expression of eight putative prognostic proteins assessed by Western blot in the discovery set of samples. NL, Normal liver (white boxes); HB, Hepatoblastoma (black circles).
  • B Representative Western blot of 3 NL and 6 HB (3 C1 and 3 C2) of the 3 selected prognostic biomarkers.
  • C Kaplan-Meier plot of Event Free Survival of training set patients classified according to the expression of the 3 prognostic biomarkers selected by Western Blot.
  • the number of biomarkers altered in each patient (0, 1 , 2 or 3 BM means 0, 1 , 2 or 3 biomarkers altered) was strongly associated with the prognosis of HB patients and survival curves revealed the complementarity of the different biomarkers.
  • the alteration of CKAP4 and C1 QBP was defined as overexpression of the biomarkers more than or equal than two-fold expression of the adjacent healthy liver.
  • the alteration of CRYL1 was defined as under-expression of the protein in an amount less than the half of that determined for the adjacent healthy liver.
  • BM biomarker.
  • Fig. 4 Correlation between protein and mRNA expression of the three prognostic biomarkers, CKAP4, C1 QBP and CRYL1. Protein and gene expression were assessed by Western Blot and Human Transcriptome Array of Affymetrix, respectively. Green dots represented tumours of the C1 subtype and good prognosis; Red spots, represent tumours of the C2 subtype and poor prognosis.
  • Fig. 5 Definition of the 3-protein signature.
  • A Method for determining the 3- protein signature. First, a calculation of a global score of the immunostaining for each marker taking into account the percentage of stained tumour cells as well as the intensity of the staining is needed. Second, the alteration of each biomarker should be determined taking into account a cut-off of the global staining score which was established by using non-tumour healthy liver staining as a reference. Thus, CKAP4 and C1 QBP immunostainings were considered as“altered” when their global staining score was >12 (2 times the NL maximum value) and CRYL1 when no expression was detected.
  • the 3-protein signature is obtained for a specific patient by adding the number of the 3 biomarkers altered in the tumour (3-protein score rank: 0-3).
  • B Global score plots of the three different prognostic biomarkers in non-tumour (NT) and tumour (T) samples of the 144 patients of the test set. The cut-off chosen for each biomarker is represented as a red line. Taking into account the different cut-off values, 49, 48 and 11 % of the paediatric patients with liver cancer have C1 QBP, CKAP4 and CRYL1 altered in their tumours.
  • C Representative images of the cytoplasmic immunostaining of the three biomarkers in Normal healthy adjacent liver (NL) and in hepatoblastoma tissues with normal and altered expression.
  • Fig. 6 Survival analysis of the 3-protein signature in the 144 childhood liver cancer patients. Kaplan-Meier plots of EFS (left) and OS (right) of the three biomarkers individually. Abbreviations, EFS, event-free survival; OS, overall survival.
  • Fig. 7 Impact of the 3-protein signature on the current clinical OH IC-HS stratification
  • Top panel Kaplan-Meier plots of Event Free Survival (right) and Overall survival (left) of 128 patients of the training set classified according to the expression of current clinical stratification system OH IC-HS (Meyers et al., 2017).
  • Top middle panel Kaplan-Meier plots of Event Free Survival (right) and Overall survival (left) of 20 patients of the training set clinically classified as low or very low risk and re-stratified according to the 3-protein signature.
  • Bottom middle panel Kaplan-Meier plots of Event Free Survival (right) and Overall survival (left) of 66 patients of the training set clinically classified as intermediate risk and re-stratified according to the 3-protein signature.
  • Bottom Kaplan-Meier plots of Event Free Survival (right) and Overall survival (left) of 32 patients of the training set clinically classified as high risk and re- stratified according to the 3-protein signature.
  • Fig. 8 The 3-protein signature survival analysis in non-treated diagnostic specimens. Kaplan-Meier plots of Event Free Survival (right) and Overall survival (left) of 42 patients of the training set from which non-treated specimens were studied, stratified according to a simplified 3-protein signature (“0 BM”, none of the 3 biomarkers was altered;“1 or 2 or 3”, at least 1 or 2 or 3 biomarker/s was altered).
  • Fig. 11 Kaplan-Meier plots of Event free survival of 30 adult patients with HCC treated by surgical resection and stratified according to the levels of 2 out of 3 biomarkers of the 3 protein signature.
  • CRYL1 was down-regulated in a unique case with poor outcome but no follow-up data; thus, no survival study taking into account CRYL1 could be performed.
  • EFS event-free survival
  • p p-value obtained in the log- rank test.
  • Fig. 12 Kaplan-Meier plots of Event free survival of 30 adult patients with HCC treated by surgical resection and stratified according to a simplified 3 -protein signature. EFS, event-free survival; p, p-value obtained in the log-rank test.
  • the present invention concerns a method or process of quantitatively and qualitatively analyze at least one of the biomarkers disclosed herein or any combination thereof in a sample previously obtained from a patient diagnosed for a, preferably primary, liver tumor, so that to determine the prognosis of said liver tumor in a patient, thus proposing in combination with the clinical stratification, preferably at diagnosis or alone after surgery, the most appropriate treatment.
  • the“3-protein signature” is the combination of the three biomarkers disclosed herein that may be used in alone or may be used in combinations of two or three to further improve the prognosis of the patient with liver cancer and thus the patient's clinical evolution, treatment and outcome.
  • liver tumor By“liver tumor”,“liver cancer” or“hepatic tumor”, it is meant a tumor originating from the liver of a patient, which is a malignant tumor (comprising cancerous cells), as opposed to a benign tumor (non-cancerous) which is explicitly excluded.
  • Malignant liver tumors encompass mainly two kinds of tumors: hepatoblastoma (HB) or hepatocellular carcinoma (HCC). The prognosis of these two tumor types can be determined by using the presently reported biomarkers.
  • a patient is a child i.e., if it is a human host who is under 20 years of age. Therefore, in a particular embodiment, the liver tumor is a pediatric HB or a pediatric HCC. In another embodiment, the liver tumor is an adult HCC.
  • the biological sample of the present disclosure is a substance or a mixture of the substances that contain or is expected to contain/express one or more of the present biomarkers, and includes cells, tissues or bodily fluids from an organism, particularly human, for example, whole blood, urine, plasma, and serum, but is not limited thereto. Also the sample includes cells or tissues cultured in vitro as well as those derived directly from an organism. Various samples may be used for the detection of HCC or HB markers according to the present disclosure. In one embodiment, urine, whole blood, plasma and/or blood serum can be used. In other embodiment, the liver tissues/cells or in vitro cell cultures from an organism of interest, where HCC has developed or HCC is plausible or likely to be developed, may be used, but the samples are not limited thereto.
  • the fractions or derivatives of the blood, cells or tissues are included. When cells or tissues are used, lysates thereof may also be used.
  • the markers according to the present disclosure are primarily defined according to the expression level, the difference in the expression level or the changes in the expression level at the mRNA or protein level as compared to the reference sample through various quantitative, semiquantiative and/or qualitative analysis methods known in the art.
  • the quantitative, semiquantitative and qualitative analysis of the markers for HCC and HB prognosis may be done by various methods known in the art that can detect the proteins and mRNA quantitatively and qualitatively.
  • the methods include a western blot, an ELISA, a radioimmunoassay, an immunodiffusion, an Immunoelectrophoresis, an immunostaining, an immunoprecipitation, a complement fixation assay, a system based on tailed beads, a binding with a tailed antibody in solution/suspension and a detection by flow cytometry, or a mass spectrometry, and the like.
  • an immunoassay using sandwich system like ELISA (Enzyme Linked Immuno Sorbent Assay), or RIA (Radio Immuno Assay) and the like may be used for quantitative and/or qualitative detection of the present markers.
  • a solid substrate/support such as a glass, a plastic (for example, polystyrene), polysaccharides, a bead, a nylon or nitrocellulose membrane or a microplate well to form a complex and the complex is then allowed to react with an second antibody that is usually labeled with agents that can be detected directly or indirectly such as radioactive substances like 3H or 1251, fluorescent materials, chemiluminescent substances, hapten, biotin, or digoxygenin and the like.
  • agents that can be detected directly or indirectly such as radioactive substances like 3H or 1251, fluorescent materials, chemiluminescent substances, hapten, biotin, or digoxygenin and the like.
  • the labeling materials are conjugated with an enzyme such as horseradish peroxidase, alkaline phosphatase, or maleate dehydrogenase that is able to produce colors or color changes or illuminate in the presence of appropriate substrates.
  • an enzyme such as horseradish peroxidase, alkaline phosphatase, or maleate dehydrogenase that is able to produce colors or color changes or illuminate in the presence of appropriate substrates.
  • Other methods based on immune reaction may also be used.
  • an Immuno Electrophoresis such as an Ouchterlony plate, a Western blot, a Crossed IE, a Rocket IE, a Fused Rocket IE, or an Affinity IE, which can detect the markers simply by antigen-antibody reaction may be used.
  • the agents or materials that may be used in the methods described above are known the art.
  • the markers may be detected through an antigen-antibody reaction, or a reaction with a substrate, nucleic acid or peptide aptamers, receptors or ligands that specifically recognize the present markers, or cofactors or using mass spectrometry.
  • the agents or materials that bind or interact specifically with the markers of the present disclosure can be utilized by means of chip or with nanoparticles.
  • the immunoassay or immunostaining methods as described above are disclosed in the following literatures : Enzyme Immunoassay, E.; Gaastra, W., Enzyme-linked immunosorbent assay(ELISA), in Methods in Molecular Biology, Vol. 1 , Walker, J.M. ed., Flumana Press, NJ, 1984 etc.
  • the intensities of the signals generated by the immunoassay mentioned above are then analyzed, namely compared with the signals from appropriate controls for the determination.
  • methods for measuring the expression level of any of the biomarkers disclosed herein by using a material that detects at least one of presence, amount, and abundance pattern of mRNA transcribed by the gene and/or a protein encoded by the gene may also be used.
  • the material for measuring the expression level of the gene is at least one of a primer, a probe, an aptamer, and an antisense which are specifically bound to at least one selected from the group consisting of a nucleotide sequence of the gene, a complementary sequence thereof, a fragment of the nucleotide and a complementary sequence thereof.
  • the material for measuring the expression level of the gene is at least one selected from oligopeptides, monoclonal antibodies, polyclonal antibodies, chimeric antibodies, antibody fragments, ligands, peptide nucleic acids (PNA), aptamers, avidity multimers, and peptidomimetics which specifically bind to at least one of a polypeptide encoded by a nucleotide sequence of the gene, a polypeptide encoded by a complementary sequence thereto, and a polypeptide encoded by a fragment of the nucleotide sequence.
  • PNA peptide nucleic acids
  • the material for measuring the expression level of the gene is a detection reagent of measuring a gene expression by at least one method of a reverse transcription polymerase chain reaction, a competitive polymerase chain reaction, a real-time polymerase chain reaction, a nuclease protection assay (RNase, S1 nuclease assay), an in situ hybridization method, a DNA microarray method, northern blotting, western blotting, an enzyme linked immuno sorbent assay (ELISA), a radioimmunoassay, an immunodiffusion method, Immunoelectrophoresis, a tissue immuno staining, an immunoprecipitation assay, a complement fixation assay, an FACS, a mass spectrometry and a protein microarray.
  • CKAP4 is understood as “cytoskeleton associated protein 4” (Gene ID: 10970 for human with the following Gene aliases: p63; CLIMP-63; ERGIC-63) and “63-kDa cytoskeleton-linking membrane protein” (UniProtKB ID: Q07065).
  • CKAP4 has Gene ID: 216197, it is also known as P63, CLIMP-63, 5630400A09Rik and has the protein UniProtKB ID: Q8BMK4).
  • CKAP4 has Gene ID: 100523493.
  • CKAP4 has Gene ID: 362859 and has the protein UniProtKB ID: D3ZH41 (D3ZH41_RAT).
  • C1 QBP is understood as “complement C1 q binding protein” gene (gene ID: 708 for human with the following gene aliases: p32; HABP1 ; gC1 qR; GC1QBP; SF2p32; gC1 Q-R; COXPD33 or the“complement component 1 Q subcomponent-binding protein, mitochondrial” protein (UniProtKB ID: Q07021 for human).
  • C1 QBP has Gene ID: 12261 , it is also known as AA407365, AA986492, D11Wsu182e, HABP1 , P32, gCI qBP and has the protein UniProtKB ID: Q8R5L1 (Q8R5L1_MOUSE).
  • C1 QBP has Gene ID: 334619 it is also known as fa14h03, sb:cb785, si:ch1073-329n19.2, wu:fa14h03, zgc:110137.
  • C1 QBP has Gene ID: 29681 , it is also known as Habpl , gC1 qR and has the protein UniProtKB ID: 035796 (C1 QBP RAT).
  • C1 QBP has Gene ID: 110256103.
  • CRYL1 is understood as“crystallin lambda 1” gene (Gene ID: 51084 for human with the following gene aliases: GDH; HEL30; lambda-CRY) and“Lambda-crystallin homolog” protein (UniProtKB: Q9Y2S2 for human).
  • CRYL1 has Gene ID: 68631 it is also known as 1110025H08Rik, A230106J09Rik, C85932, gul3dh and has the protein UniProtKB ID: Q99KP3 (CRYL1 MOUSE).
  • CRYL1 In zebrafish, CRYL1 has Gene ID: 751596, it is also known as im:6895749, zgc:152659. In rat, CRYL1 has Gene ID: 290277. In pig, CRYL1 has Gene ID: 396914, it is also known as CRY, GuIDH and has the protein UniProtKB ID: Q8SQ26 (CRYL1_PIG).
  • the term “event-free-survival (EFS)” is understood as the length of time after primary treatment for a cancer ends that the patient remains free of certain complications or events that the treatment was intended to prevent or delay. These complications or events included cancer-related death of the patient as well as any particular kind of cancer progression and tumor spread such as tumor recurrence, metastasis in any organ, tumor growth in the blood vessels, etc.
  • the term“overall-survival” is understood as the length of time from either the date of diagnosis or the start of treatment for a disease, such as cancer, that patients diagnosed with the disease are still alive.
  • the term“prognosis of a hepatoblastoma (HB) or a hepatocellular carcinoma (HCC)” is understood as a medical term for predicting the likelihood of survival of a patient with malignant liver cancer.
  • the prognosis of HB is associated with the presence of different clinical parameters at diagnosis such as patient’s age, serum alpha-fetoprotein levels, PRETEXT system (pre-treatment extent of disease), presence of metastasis and tumor spreading (i.e. intragrowth blood vessels, multifocality, tumor rupture, contiguous extrahepatic growth, caudate and lymph node involvement, metastasis).
  • the prognosis of adult HCC is associated with the liver function (Child-Pugh scale), portal pressure, serum bilirubin, patient performance status, number of tumor nodules in the liver, presence of portal invasion, extrahepatic spread, presence of diabetes and the liver transplant consideration. Moreover, differentiation degree of tumor cells, presence of tumor satellites and microvascular invasion observed in the tumor specimen have been also associated with the prognosis of HCC patients, The main epithelial component in HB specimens has been also associated with the prognosis of HB patients. In the context of the present invention, the term “negative clinical evolution” is understood as poor prognosis or how the disease behaves over time in an unfavorable manner. Accordingly, patient during follow-up suffer certain complications or events related to cancer progression tumor spread, tumor recurrence, metastasis in any organ, tumor growth in the blood vessels among other which ultimately can derive in the death of the patient because of the disease.
  • DFS disease-free survival
  • PFS progression-free survival
  • a disease such as cancer
  • control sample is understood as the healthy biological sample such as non-tumor tissue that could be obtained from a healthy individual or from a liver cancer patient.
  • the term“reference value” is understood as the value of the level of staining and/or concentration and/or the presence of the biomarker in the“control sample” or obtained thereof.
  • the term “altered” is understood as a biomarker from which level of staining and/or concentration and/or the presence of the biomarker in a biological sample is different from the control sample.
  • Liver cancer is a disease with an increasing worldwide incidence and a poor prognosis.
  • the most frequent liver cancer is the Hepatocellular Carcinoma (HCC) which is the sixth most commonly occurring cancer in the world, the third leading cause of cancer mortality and it is mainly diagnosed in adults with an underlying liver disease.
  • HCC Hepatocellular Carcinoma
  • HB hepatoblastoma
  • a curative treatment is possible by combining chemotherapy and surgery. Nevertheless, 20% of HB patients do not survive cancer and survivors can be affected by serious side effects related to chemotherapy.
  • CHIC clinical stratification of HB patients relies on clinical parameters including pre-treatment extension of the tumor, patient age, serum AFP levels, multifocal ity, presence of distant metastases and different degrees of tumor spread such as tumor rupture, blood tumor growth, etc.
  • Pediatric HCC is a dismal disease, only approximately 30% of the patients survive the disease. Their prognosis is mainly linked to the tumor stage at diagnosis and its resectability. pHCC is the second most common liver tumor in children being most of the cases diagnosed after 10 years of age, it is the main hepatic tumor in adolescents and usually it is a dismal disease because usually its diagnosis is at advanced tumor stages when no chance of cure is possible.
  • the current clinical stratification for HB patients provides four groups of patients according to their prognosis: very low, low, intermediate and poor risk patients, being defined very low and low patients as low risk in the figure.
  • the problem lies in the intermediate and poor prognostic groups, said problem being the uncertainty of the severity of the disease within said groups since they comprise patients with a potentially good prognosis as well as patients with a poor prognosis that are not possible to identify throughout clinical criteria.
  • a combined chemotherapy and surgery is administered to all of the patients pertaining to said groups giving raise to severe side effects in those patients who most probably were not in the need of the same therapy.
  • we herein provide a 3-protein signature as an independent predictor of prognosis optionally to be used together with the CHIC clinical stratification.
  • CRYL1 was not performed by the survival study with altered CRYL1 because of its low incidence (only 1 patient out of 88 had a loss of CRYL1 expression).
  • the 3-protein signature could be assessed not only at protein level but also at mRNA level (See Figure 4 and methodology of gene expression (mRNA) assessment in the last part of the examples section). In that regard, a significant correlation was observed between the quantitative protein levels of CKAP4, C1 QBP and CRYL1 assessed by Western blot and their gene expression determined by Human Transcriptome Array (Affymetrix). Thus, the 3-protein signature could be also named 3-gene signature which is also correlated with aggressive C2 tumour subtype and accordingly, patient prognosis.
  • detecting the level and/or concentration and/or the presence of at least one biomarker selected from the group consisting of CKAP4, C1 QBP and CRYL1 at a protein or RNA level in an isolated sample from a subject diagnosed with a hepatoblastoma (HB)) or a hepatocellular carcinoma (HCC) in children or adults is particularly useful for the prognosis prediction of said subject.
  • detecting the level and/or concentration and/or the presence of at least one biomarker selected from the group consisting of CKAP4, C1 QBP and CRYL1 at a protein or RNA level in an isolated sample from a subject diagnosed with a liver cancer is particularly useful for the prognosis of said subject and to decide treatment after surgery.
  • a first aspect of the invention refers to a method for determining the prognosis of a subject diagnosed with liver cancer, comprising: a. detecting the level and/or concentration and/or the presence of at least one biomarker selected from the group consisting of CKAP4, C1 QBP and CRYL1 at a protein or RNA level in an isolated sample from said subject diagnosed with any of said cancers; and
  • the subject preferably a human subject, most preferably an adult or a children, is diagnosed with a hepatoblastoma (HB) or
  • the method refers to a change in the level and/or concentration and/or the presence of at least biomarker CKAP4 in the subject compared to the control or reference value.
  • the method refers to a change in the level and/or concentration and/or the presence of at least biomarker C1 QBP in the subject compared to the control or reference value.
  • the method refers to a change in the level and/or concentration and/or the presence of at least biomarker CRYL1 in the subject compared to the control or reference value.
  • the method refers to a change in the level and/or concentration and/or the presence of at least the biomarker CKAP4 and the change is the increased concentration and/or levels and/or presence of at least the biomarker CKAP4 in the subject compared to the control or reference value, wherein said increased concentration and/or levels and/or presence is indicative of a negative clinical evolution of the subject.
  • the method refers to a change in the level and/or concentration and/or the presence of at least the biomarker C1 QBP and the change is the increased concentration and/or levels and/or presence of at least the biomarker C1 QBP in the subject compared to the control or reference value, wherein said increased concentration and/or levels and/or presence is indicative of a negative clinical evolution of the subject.
  • the method refers to a change in the level and/or concentration and/or the presence of at least the biomarker CRYL1 and the change is the decreased or reduced concentration and/or levels and/or presence of at least the biomarker CRYL1 in the subject compared to the control or reference value, wherein said decreased or reduced concentration and/or levels and/or presence is indicative of a negative clinical evolution of the subject.
  • the method refers to a change in the level and/or concentration and/or the presence of at least the biomarkers CKAP4 and C1 QBP, and the change is the increased concentration and/or levels and/or presence of at least the biomarkers CKAP4 and C1 QBP in the subject compared to the control or reference value, and wherein said increased concentration and/or levels and/or presence is indicative of a negative clinical evolution of the subject.
  • the method refers to a change in the level and/or concentration and/or the presence of at least the biomarkers CKAP4 and CRYL1 , and the change is the increased concentration and/or levels and/or presence of at least the biomarkers CKAP4, and the reduced concentration and/or levels and/or presence of at least the biomarkers CRYL1 in the subject compared to the control or reference value, and wherein said change in the concentration and/or levels and/or presence is indicative of a negative clinical evolution of the subject.
  • the method refers to a change in the level and/or concentration and/or the presence of at least the biomarkers C1 QBP and CRYL1 , and the change is the increased concentration and/or levels and/or presence of at least the biomarkers C1 QBP, and the reduced concentration and/or levels and/or presence of at least the biomarkers CRYL1 in the subject compared to the control or reference value, and wherein said change in the concentration and/or levels and/or presence is indicative of a negative clinical evolution of the subject.
  • the method refers to a change in the level and/or concentration and/or the presence of at least the 3-protein/gene signature comprising of biomarkers: CKAP4, C1 QBP and CRYL1 , wherein the change is the increased concentration and/or levels and/or presence of at least the biomarkers CKAP4 and C1 QBP in the subject compared to the control or a reference value and the decreased concentration and/or levels and/or presence of biomarker CRYL1 in the subject compared to the control or a reference value, and wherein said increased and decreased concentration and/or levels and/or presence is indicative of a negative clinical evolution of the subject.
  • the concentration of at least the biomarkers CKAP4 and/or CRYL1 is determined in an isolated tissue liver sample and the concentration of at least the biomarkers C1 QBP is determined in an isolated tissue liver sample or in a blood, serum or plasma sample.
  • the detection is performed by at least one of an antigen- antibody reaction- or a mass spectrometry-based techniques.
  • the detection of the concentration or the presence of the biomarkers at the protein level is performed by at least one of a western blot, an ELISA, a radioimmunoassay, an immunodiffusion assay, and immunoelectrophoresis, an immunostaining, an immunoprecipitation, a complement fixation assay, a FACS, a mass spectrometry, or a protein microarray.
  • the material for measuring the expression level of any of the biomarkers is a material that detects at least one of presence, amount, and abundance pattern of mRNA transcribed by the gene and/or a protein encoded by the gene.
  • the material for measuring the expression level of the gene is at least one of a primer, a probe, an aptamer, and an antisense which are specifically bound to at least one selected from the group consisting of a nucleotide sequence of the gene, a complementary sequence thereof, a fragment of the nucleotide and a complementary sequence thereof.
  • the material for measuring the expression level of the gene is at least one selected from oligopeptides, monoclonal antibodies, polyclonal antibodies, chimeric antibodies, antibody fragments, ligands, peptide nucleic acids (PNA), aptamers, avidity multimers, and peptidomimetics which specifically bind to at least one of a polypeptide encoded by a nucleotide sequence of the gene, a polypeptide encoded by a complementary sequence thereto, and a polypeptide encoded by a fragment of the nucleotide sequence.
  • PNA peptide nucleic acids
  • the material for measuring the expression level of the gene is a detection reagent of measuring a gene expression by at least one method of a reverse transcription polymerase chain reaction, a competitive polymerase chain reaction, a real-time polymerase chain reaction, a nuclease protection assay (RNase, S1 nuclease assay), an in situ hybridization method, a DNA microarray method, northern blotting, western blotting, an enzyme linked immuno sorbent assay (ELISA), a radioimmunoassay, an immunodiffusion method, immunoelectrophoresis, a tissue immuno staining, an immunoprecipitation assay, a complement fixation assay, an FACS, a mass spectrometry and a protein microarray.
  • the 3-protein signature defined in the present invention is useful for predicting the prognosis of the main liver tumors not only those found in childhood but also those that arise in adulthood. This invention has particular relevance because of the high and increasing incidence of adult HCC, the sixth most common tumor in the world.
  • the 3-protein/gene signature as an independent prognostic factor of liver cancer patients, preferably of childhood and adulthood liver cancer patients, diagnosed with a hepatoblastoma (HB), or a hepatocellular carcinoma (HCC) that for childhood liver cancer patients is a useful tool to improve prognostic prediction together with the CHIC clinical stratification (Table 10. Multivariate analysis).
  • HB hepatoblastoma
  • HCC hepatocellular carcinoma
  • a second aspect of the invention refers to the method of the first aspect of the invention or of any of its preferred embodiments, wherein the method is used as an independent prognostic factor of liver cancer patients, preferably of liver cancer patients diagnosed with a hepatoblastoma (HB) or a hepatocellular carcinoma (HCC), or can be use together with the clinical stratification, or with any specific clinical data from the subject such as patient’s age, vascular invasion, any kind of tumor spreading, tumor multifocality, serum AFP levels, presence of satellites, BCLC stage, main HB epithelial component and/or HCC differentiation degree.
  • HB hepatoblastoma
  • HCC hepatocellular carcinoma
  • a third aspect of the invention refers to a method of treatment of a subject diagnosed with liver cancer patients, preferably of liver cancer patients diagnosed with a hepatoblastoma (HB) or a hepatocellular carcinoma (HCC), which comprises determining the clinical evolution of the subject by using the method of the first aspect of the invention or of any of its preferred embodiments, and administering a suitable treatment of liver cancer in case the method indicates a negative clinical evolution of the subject.
  • HB hepatoblastoma
  • HCC hepatocellular carcinoma
  • said suitable treatment is selected from the group consisting of surgical approaches (surgical resection, cadaveric or living donor liver transplantation), ablation, Transcatheter arterial chemoembolization (TACE) cisplatine, doxorubicin, carboplatin, sorafenib, Ifosfamide, fluorouracil, vincristine, etopside, pirarubicin, pirarubicin, or any combinations thereof.
  • surgical approaches surgical resection, cadaveric or living donor liver transplantation
  • ablation Transcatheter arterial chemoembolization (TACE) cisplatine
  • doxorubicin carboplatin
  • sorafenib sorafenib
  • Ifosfamide fluorouracil
  • vincristine etopside
  • pirarubicin pirarubicin
  • a fourth aspect of the invention refers to an in vitro use of a kit for the prognosis of a liver cancer in a subject diagnosed with liver cancer, comprising an agent to detect the level and/or concentration and/or the presence of at least one biomarker selected from the group consisting of CKAP4, C1 QBP and CRYL1 or any combination thereof, wherein prognosis is understood as the clinical evolution of the subject in terms of event-free-survival (EFS), overall-survival (OS), DFS, disease-free survival or PFS, progression-free survival, tumor recurrence and/or any of the clinical and tumor features associated to prognosis such as patient’s age, vascular invasion, any kind of tumor spreading, tumor multifocality, serum AFP levels, presence of satellites, BCLC stage, main HB epithelial component and/or FICC differentiation degree.
  • EFS event-free-survival
  • OS overall-survival
  • DFS disease-free survival or PFS
  • progression-free survival tumor
  • the subject is diagnosed with a hepatoblastoma (HB) or a hepatocellular carcinoma (FICC).
  • HB hepatoblastoma
  • FICC hepatocellular carcinoma
  • the kit comprises agents to detect the level of the 3-protein/gene signature comprising at least the three following biomarkers: CKAP4, C1 QBP and CRYL1.
  • agents for measuring the expression level of any of the biomarkers is a material that detects at least one of presence, amount, and abundance pattern of mRNA transcribed by the gene and/or a protein encoded by the gene may be used.
  • the material for measuring the expression level of the gene is at least one of a primer, a probe, an aptamer, and an antisense which are specifically bound to at least one selected from the group consisting of a nucleotide sequence of the gene, a complementary sequence thereof, a fragment of the nucleotide and a complementary sequence thereof.
  • the material for measuring the expression level of the gene is at least one selected from oligopeptides, monoclonal antibodies, polyclonal antibodies, chimeric antibodies, antibody fragments, ligands, peptide nucleic acids (PNA), aptamers, avidity multimers, and peptidomimetics which specifically bind to at least one of a polypeptide encoded by a nucleotide sequence of the gene, a polypeptide encoded by a complementary sequence thereto, and a polypeptide encoded by a fragment of the nucleotide sequence.
  • PNA peptide nucleic acids
  • the material for measuring the expression level of the gene is a detection reagent of measuring a gene expression by at least one method of a reverse transcription polymerase chain reaction, a competitive polymerase chain reaction, a real-time polymerase chain reaction, a nuclease protection assay (RNase, S1 nuclease assay), an in situ hybridization method, a DNA microarray method, northern blotting, western blotting, an enzyme linked immuno sorbent assay (ELISA), a radioimmunoassay, an immunodiffusion method, Immunoelectrophoresis, a tissue immuno staining, an immunoprecipitation assay, a complement fixation assay, an FACS, a mass spectrometry and a protein microarray.
  • the agent is to detect the concentration and/or presence or absence of the biomarkers at a protein level.
  • the agent to detect the concentration and/or presence or absence of the biomarkers at the protein level is an agent which is employed for a western blot, an ELISA, a radioimmunoassay, an immunodiffusion assay, and Immunoelectrophoresis, an immunostaining, an immunoprecipitation, a complement fixation assay, a FACS, a mass spectrometry, or a protein microarray.
  • the agent to detect the concentration and/or the presence or absence of the biomarkers at the protein level is a monoclonal antibody, a polyclonal antibody, a substrate, an aptamer, an avimer, a peptidomimetic, a receptor, a ligand or a cofactor.
  • a monoclonal antibody a polyclonal antibody
  • a substrate an aptamer, an avimer, a peptidomimetic, a receptor, a ligand or a cofactor.
  • liver cancer blood and/or tissue samples from 368 individuals with different stages of liver disease, including 175 HCC patients, 108 cirrhotic patients without primary liver cancer, 77 chronic hepatitis patients, and 8 individuals with no liver disease. Of these, 88 patients with HCC with tissue samples were included in the study to assess the 3 biomarkers of the 3-protein signature by immunohistochemistry. In the table 3, there is a summary of the main clinical and pathological features of the adult liver cancer patients included in the immunohistochemistry studies.
  • T/NT T vs. NT is fold change (FC); Criteria: LF p-value ⁇ 0.0005; DIGE p-value ⁇ 0.001 ; (*) When a protein was found by both techniques, LF FC was chosen.
  • C1 QBP immunostaining protein
  • CKAP4 showed a cytoplasmic, finely granular staining pattern, on both non-tumor hepatocytes and tumor cells, with different intensities (negative, weak and strong). Most cases showed a similar and diffuse intensity all over the examined tissue. No staining of nuclei or other tissue cells was seen.
  • C1 QBP showed also a cytoplasmic, granular pattern, with a more varied shade of intensities (negative, weak, moderate and intense).
  • Non tumor liver was either negative or showed a faintly positive cytoplasmic staining of hepatocytes. No staining of other tissue elements was noted. CRYL stained both cytoplasm and nuclei of tumorl cells. The intensity of staining was negative, weak, moderate or intense. Non-tumor hepatocytes showed a similar pattern of staining with a tendency to increase nuclei intensity in periportal areas. No staining of other tissue elements was noted.
  • the global score determined by Immunohistochemistry (IHC) for the non-tumor and tumor hepatocytes (NT and T) for the different biomarkers is shown in Figure 5B.
  • a representative staining for each marker for non-tumour as well as for an altered and non-altered tumours are shown in Figure 5C.
  • Table 9A Association of the 3 proteins with clinical, pathological and molecular features. Chi-square or Fisher Exact test p-value is shown depending on statistical convenience.
  • Table 9B Association of the 3 proteins with patient age at diagnosis. P-val, unpaired t-test p-value.
  • CKAP4 has a statistical significance concerning the prognosis of pediatric liver cancer patients in terms of EFS and OS ( Figure 6).
  • Figure 6 For the remaining markers, there is a trend in which cases with C1 QBP or CRYL1 altered have a worse outcome, except for CRYL1 and OS (see figure 6).
  • HTA data was also correlated with qPCR data obtained by using the primers of the table 14, the RHOT2 as a reference gene and the 2 _DDa method to determine gene expression Plasma expression of C1QBP in childhood and adulthood patients with liver cancer
  • ELISA was performed using 30 plasma samples from pediatric and aduthood patients with liver cancer, including cases with HB and HCC as well as 7 healthy patients. Patients with liver cancer were stratified according to the presence of prognostic features: 15 were defined as good prognosis whereas 15 with poor prognosis. Childhood patients with tumors with features of poor prognosis had metastasis and/or multifocal tumors and/or advanced PRETEXT stage and/or AFP >10 6 ng/mL and/or more than 3 years and/or pHCC. Adult patients with tumors with features of poor prognosis had an advanced BCLC tumor stage and/or multifocal tumors and/or tumor recurrence. Childhood and adulthood patients classified as“good prognosis” did not have any criteria associated with poor outcome.

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Abstract

La présente invention concerne une méthode ou un processus d'analyse quantitative et qualitative d'au moins l'un des biomarqueurs de l'invention ou de toute combinaison de ces derniers dans un échantillon précédemment obtenu chez un patient diagnostiqué présentant une tumeur hépatique, de manière à déterminer le pronostic de ladite tumeur hépatique chez un patient, ce qui permet de proposer, en combinaison ou non avec la stratification clinique, le traitement le plus approprié et d'adopter la stratégie thérapeutique la plus appropriée.
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CN113517023A (zh) * 2021-05-18 2021-10-19 柳州市人民医院 与性别相关的肝癌预后标志性因素及其筛选方法

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