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WO2019072888A1 - Méthodes de prédiction de la réponse thérapeutique dans le cancer hépatocellulaire - Google Patents

Méthodes de prédiction de la réponse thérapeutique dans le cancer hépatocellulaire Download PDF

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Publication number
WO2019072888A1
WO2019072888A1 PCT/EP2018/077554 EP2018077554W WO2019072888A1 WO 2019072888 A1 WO2019072888 A1 WO 2019072888A1 EP 2018077554 W EP2018077554 W EP 2018077554W WO 2019072888 A1 WO2019072888 A1 WO 2019072888A1
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WIPO (PCT)
Prior art keywords
subject
responder
endocan
expression level
hepatocellular carcinoma
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PCT/EP2018/077554
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English (en)
Inventor
Philippe Lassalle
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Centre National de la Recherche Scientifique CNRS
Institut Pasteur de Lille
Institut National de la Sante et de la Recherche Medicale INSERM
Institut Pasteur
Universite de Lille
Original Assignee
Centre National de la Recherche Scientifique CNRS
Institut Pasteur de Lille
Institut National de la Sante et de la Recherche Medicale INSERM
Institut Pasteur
Universite de Lille
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Publication of WO2019072888A1 publication Critical patent/WO2019072888A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • G01N33/57525—
    • 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
    • G01N33/68—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids
    • 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 invention relates to methods for predicting hepatocellular carcinoma treatment response.
  • Hepatocellular carcinoma also called hepatocarcinoma, is the sixth most common neoplasm and the third cause of cancer death worldwide.
  • HCC develops in most cases within an established background of chronic hepatitis or cirrhosis related to various origins including hepatitis virus infection, high alcohol intake or metabolic diseases.
  • the prognosis for patients with HCC is poor with an overall 5 year-survival rate of less than 5%.
  • the 5-year survival rate is higher than 80% for small resectable HCC in patients with well-compensated cirrhosis and decreases to a median survival of 9.5 months for unresectable or metastatic disease.
  • methods for predicting hepatocellular carcinoma treatment response is of crucial importance on patient survival.
  • the present invention relates to methods for determining whether a subject afflicted with hepatocellular carcinoma will be a responder or a non-responder to anti-angiogenic treatment.
  • one aspect of the invention relates to a method of determining whether a subject afflicted with hepatocellular carcinoma (HCC) will be a responder or a non-responder to anti-angiogenic treatment comprising the step of measuring the expression level of endocan in a biological sample obtained from said subject.
  • HCC hepatocellular carcinoma
  • the invention relates to a method of determining whether a subject afflicted with hepatocellular carcinoma (HCC) will be a responder or a non-responder to sorafenib treatment comprising the step of measuring the expression level of endocan in a biological sample obtained from said subject.
  • HCC hepatocellular carcinoma
  • the method of the invention is performed before the anti- angiogenic treatment.
  • the method of the invention is performed during the anti- angiogenic treatment.
  • subject denotes a mammal.
  • a subject refers to any subject (preferably human) afflicted with hepatocellular carcinoma.
  • the term “subject” refers to any subject (preferably human) undergoing a hepatocellular carcinoma therapy such as surgical resection and radio frequency ablation (RFA).
  • RFA radio frequency ablation
  • hepatocellular carcinoma or "HCC” has its general meaning in the art and refers to hepatocellular carcinoma or hepatocarcinoma such as revised in the World Health Organisation Classification C22.0 (ICD-10 Version:2010).
  • endocan has its general meaning in the art and refers to neoangiogenesis- related molecule, an endothelium derived soluble dermatan sulfate proteoglycan.
  • endocan also refers to ESM-1, the endothelial cell specific molecule (Lassalle et al, 1996).
  • anti-angiogenic treatment refers to at least one administration of anti- angiogenic compound.
  • anti-angiogenic treatment also refers to 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 administration of anti-angiogenic compound.
  • serafenib treatment refers to at least one sorafenib administration.
  • sorafenib treatment also refers to 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 sorafenib administration.
  • the term “sorafenib administration” refers to a dose of 200, 400, 600, 800 or 1000 mg/day of sorafenib.
  • anti-angiogenic compound has its general meaning in the art and refers to compounds used in anti-angiogenic therapy such as tyrosine kinase inhibitors, anti-angiogenic tyrosine kinase receptor (TK ) inhibitors, anti-angiogenics targeting the Vascular Endothelial Growth Factor (VEGF) and the Vascular Endothelial Growth Factor Receptors (VEGFRs) pathway such anti-VEGF antibody bevacizumab (Avastin) and VEGF receptor tyrosine kinase inhibitor (TKI) compounds such as sunitinib (Sutent), vandetanib (Zactima), pazopanib (Votrient), sorafenib (Nexavar) and cediranib, interferon therapy and anti-HER2 compounds such as Trastuzumab (herceptin) and pertuzumab.
  • TK tyrosine kinase inhibitors
  • anti- angiogenic compound refers to Sunitinib (Sutent), an anti-angiogenic TKR inhibitor of VEGFRs, platelet-derived growth factor receptors (PDGF-Rs), and c-kit.
  • tyrosine kinase inhibitor or “TKI” has its general meaning in the art and refers to any of a variety of therapeutic agents or drugs such as compounds inhibiting tyrosine kinase, tyrosine kinase receptor inhibitors (TKRI), EGFR tyrosine kinase inhibitors, EGFR antagonists.
  • tyrosine kinase inhibitor or "TKI” has its general meaning in the art and refers to any of a variety of therapeutic agents or drugs that act as selective or non-selective inhibitors of receptor and/or non-receptor tyrosine kinases. Tyrosine kinase inhibitors and related compounds are well known in the art and described in U.S Patent Publication 2007/0254295, which is incorporated by reference herein in its entirety.
  • a compound related to a tyrosine kinase inhibitor will recapitulate the effect of the tyrosine kinase inhibitor, e.g., the related compound will act on a different member of the tyrosine kinase signaling pathway to produce the same effect as would a tyrosine kinase inhibitor of that tyrosine kinase.
  • tyrosine kinase inhibitors and related compounds suitable for use in methods of embodiments of the present invention include, but are not limited to Erlotinib, sunitinib (Sutent; SU11248), dasatinib (BMS-354825), PP2, BEZ235, saracatinib, gefitinib (Iressa), erlotinib (Tarceva; OSI-1774), lapatinib (GW572016; GW2016), canertinib (CI 1033), semaxinib (SU5416), vatalanib (PTK787/ZK222584), sorafenib (BAY 43-9006), imatinib (Gleevec; STI571), leflunomide (SU101), vandetanib (Zactima; ZD6474), MK-2206 (8-[4-aminocyclobutyl)phenyl]-9-phenyl-l,2,4-triazol
  • the tyrosine kinase inhibitor is a small molecule kinase inhibitor that has been orally administered and that has been the subject of at least one Phase I clinical trial, more preferably at least one Phase II clinical, even more preferably at least one Phase III clinical trial, and most preferably approved by the FDA for at least one hematological or oncological indication.
  • inhibitors include, but are not limited to Erlotinib, Gefitinib, Lapatinib, Canertinib, BMS-599626 (AC-480), Neratinib, KRN-633, CEP-11981, Imatinib, Nilotinib, Dasatinib, AZM-475271, CP-724714, TAK-165, Sunitinib, Vatalanib, CP- 547632, Vandetanib, Bosutinib, Lestaurtinib, Tandutinib, Midostaurin, Enzastaurin, AEE-788, Pazopanib, Axitinib, Motasenib, OSI-930, Cediranib, KRN-951, Dovitinib, Seliciclib, SNS- 032, PD-0332991, MKC-I (Ro-317453; R-440), Sorafenib, ABT-869,
  • EGFR tyrosine kinase inhibitors as used herein include, but are not limited to compounds selected from the group consisting of but not limited to Erlotinib, lapatinib, Rociletinib (CO- 1686), gefitinib, Dacomitinib (PF-00299804), Afatanib, Brigatinib (AP26113), WJTOG3405, NEJ002, AZD9291, HM61713, EGF816, ASP 8273, AC 0010.
  • antibody EGFR inhibitors examples include Cetuximab, panitumumab, matuzumab, zalutumumab, nimotuzumab, necitumumab, Imgatuzumab (GA201, RO5083945), and ABT- 806.
  • anti-angiogenic compound refers to compounds targeting the vascular endothelial growth factor (VEGF) pathway such anti-VEGF antibody bevacizumab (Avastin) and VEGF receptor tyrosine kinase inhibitor (TKI) compounds such as sorafenib (Nexavar), sunitinib (Sutent), vandetanib (Zactima), pazopanib (Votrient), cediranib, Vatalanib, Motesanib, Pazopanib, Telatinib, Linfanib, Brivanib, BIBF-1120, Dovitinib, nintedanib, EG00229, AMG-706, BAY-57-9352, BAY-43-9006, Axitinib, AEE788, BMS- 690514, XL-647, CYC116, MGCD265, OSI930, semaxinib (SU-5416), SU-6668
  • VEGF vascular
  • the term "sorafenib” has its general meaning in the art and refers to 4- [4- [ [4-chloro-3 -(trifluoromethyl)phenyl]carbamoy lamino]phenoxy] -N-methylpyridine-2- carboxamide, having the molecular formula C21H16CIF3N4O3 and accessible under the CAS registry number 284461-73-0.
  • the term “sorafenib” also refers to compound described in U.S. Patent US2009/0192200 and US 7,235,576.
  • the term "responder” refers to a subject afflicted with hepatocellular carcinoma that will respond to anti-angiogenic treatment.
  • the disease activity can be measured according to the standards recognized in the art.
  • the disease activity may be measured by clinical and physical examination, tumor, nodes and metastasis (TNM) classification, Child-Turcotte-Pugh score, Model for End-Stage Liver Disease score (MELD), Karnofsky-score evaluation, a complete blood count, hemostasis, biochemical analyses (including hepatic enzymes, lipase, and creatinine), urine analysis, disease assessment by computed tomography (CT) and progression-free survival or overall survival.
  • TPM tumor, nodes and metastasis
  • MELD Model for End-Stage Liver Disease score
  • Karnofsky-score evaluation a complete blood count
  • hemostasis including hepatic enzymes, lipase, and creatinine
  • urine analysis disease assessment by computed tomography (CT) and progression-free
  • a “responder” or “responsive” subject to an anti- angiogenic treatment refers to a subject who shows or will show a clinically significant relief in the disease when treated with anti-angiogenic compound.
  • the term “responder” also refers to a subject having longer stable disease after anti-angiogenic treatment.
  • the term “responder” also refers to a subject having longer time to progression after anti-angiogenic treatment.
  • biological sample refers to a substance of biological origin.
  • biological sample refers to any biological sample derived from the subject such as biopsy and bodily fluids samples.
  • biological sample also refers to a blood sample, a whole blood sample, a plasma sample, or a serum sample.
  • the method of the invention may further comprise a step consisting of comparing the expression level of endocan in the biological sample with a reference value, wherein detecting differential in the expression level of the endocan between the biological sample and the reference value is indicative that said subject will be a responder or a non-responder.
  • the "reference value” refers to a threshold value or a cut-off value.
  • the reference value can be a threshold value or a cut-off value.
  • a “threshold value” or “cut-off value” can be determined experimentally, empirically, or theoretically.
  • a threshold value can also be arbitrarily selected based upon the existing experimental and/or clinical conditions, as would be recognized by a person of ordinary skill in the art. The threshold value has to be determined in order to obtain the optimal sensitivity and specificity according to the function of the test and the benefit/risk balance (clinical consequences of false positive and false negative).
  • the optimal sensitivity and specificity can be determined using a Receiver Operating Characteristic (ROC) curve based on experimental data.
  • ROC Receiver Operating Characteristic
  • the person skilled in the art may compare the biomarker expression level (obtained according to the method of the invention with a defined threshold value).
  • the threshold value is derived from the biomarker expression level (or ratio, or score) determined in a biological sample derived from one or more subjects who are responders to anti-angiogenic treatment.
  • the threshold value may also be derived from biomarker expression level (or ratio, or score) determined in a biological sample derived from one or more subjects who are non-responders to anti-angiogenic treatment.
  • retrospective measurement of the biomarker expression level (or ratio, or scores) in properly banked historical subject samples may be used in establishing these threshold values.
  • the reference value may be determined by carrying out a method comprising the steps of
  • step c) classifying said biological samples in two groups for one specific arbitrary quantification value provided at step c), respectively: (i) a first group comprising biological samples that exhibit a quantification value for level that is lower than the said arbitrary quantification value contained in the said serial of quantification values; (ii) a second group comprising biological samples that exhibit a quantification value for said level that is higher than the said arbitrary quantification value contained in the said serial of quantification values; whereby two groups of biological samples are obtained for the said specific quantification value, wherein the biological samples of each group are separately enumerated;
  • step f) calculating the statistical significance between (i) the quantification value obtained at step e) and (ii) the actual clinical outcome of the subjects (i.e. response or not response) from which biological samples contained in the first and second groups defined at step f) derive; g) reiterating steps f) and g) until every arbitrary quantification value provided at step d) is tested;
  • the level of the biomarker has been assessed for 100 blood samples of 100 subjects.
  • the 100 samples are ranked according to the level of the biomarker.
  • Sample 1 has the highest level and sample 100 has the lowest level.
  • a first grouping provides two subsets: on one side sample Nr 1 and on the other side the 99 other samples.
  • the next grouping provides on one side samples 1 and 2 and on the other side the 98 remaining samples etc., until the last grouping: on one side samples 1 to 99 and on the other side sample Nr 100.
  • the p value between both subsets was calculated.
  • the reference value is then selected such as the discrimination based on the criterion of the minimum p value is the strongest.
  • the level of the biomarker corresponding to the boundary between both subsets for which the p value is minimum is considered as the reference value. It should be noted that the reference value is not necessarily the median value of levels of the biomarker.
  • a single "cut-off value thus allows discrimination between responder or non responder.
  • high statistical significance values e.g. low P values
  • high statistical significance values e.g. low P values
  • a range of values is provided. Therefore, a minimal statistical significance value (minimal threshold of significance, e.g. maximal threshold P value) is arbitrarily set and a range of a plurality of arbitrary quantification values for which the statistical significance value calculated at step g) is higher (more significant, e.g. lower P value) are retained, so that a range of quantification values is provided.
  • minimum threshold of significance e.g. maximal threshold P value
  • This range of quantification values includes a "cut-off value as described above. For example, on a hypothetical scale of 1 to 10, if the ideal cut-off value (the value with the highest statistical significance) is 5, a suitable (exemplary) range may be from 4-6. Therefore, a subject may be assessed by comparing values obtained by measuring the level of the biomarker, where values greater than 5 reveal that the subject will be a responder (or alternatively a non responder) and values less than 5 reveal that the subject will be a non responder (or alternatively a responder).
  • a subject may be assessed by comparing values obtained by measuring the level of the biomarker and comparing the values on a scale, where values above the range of 4-6 indicate that the subject will be a responder (or alternatively a non responder) and values below the range of 4- 6 indicate that the subject will be a non responder (or alternatively a non responder), with values falling within the range of 4-6 indicating an intermediate response.
  • higher expression level of endocan is indicative that the subject will be a responder to anti-angiogenic treatment
  • lower expression level of endocan is indicative that the subject will be a non-responder to anti-angiogenic treatment.
  • the reference value may correspond to the expression level determined in a biological sample derived from one or more subjects who are responders to anti-angiogenic treatment. Accordingly, when the expression level of endocan is equal or higher than the corresponding reference value, it is concluded that the subject will be a responder to anti-angiogenic treatment, and accordingly, when the expression level of endocan is lower than the corresponding reference value, its concluded that the subject will be a non-responder to anti- angiogenic treatment.
  • the reference value may correspond to the expression level determined in a biological sample derived from one or more subjects who are non-responders to anti-angiogenic treatment. Accordingly, when the expression level of endocan is higher than the corresponding reference value, it is concluded that the subject will be a responder to anti- angiogenic treatment, and accordingly, when the expression level of endocan is equal or lower than the corresponding reference value, its concluded that the subject will be a non-responder to anti-angiogenic treatment.
  • the present invention relates to a method for predicting the outcome of hepatocellular carcinoma (HCC) in a subject after anti-angiogenic treatment, comprising the steps of: i) measuring the expression level of endocan in a biological sample obtained from said subject, ii) comparing the expression level of endocan in the biological sample with a reference value, and iii) concluding that the subject have a good prognosis when the expression level determined at step i) is higher than the predetermined reference value or concluding that the subject have a poor prognosis when the expression level determined at step i) is lower than the predetermined reference value.
  • HCC hepatocellular carcinoma
  • HCC hepatocellular carcinoma
  • OS overall survival
  • EFS event-free survival
  • MFS metastasis-free survival
  • disease-free survival longer stable disease and/or longer time to progression after anti-angiogenic treatment.
  • Phor Prognosis or “Bad Prognosis” refers to a subject afflicted with hepatocellular carcinoma (HCC) receiving anti-angiogenic treatment that is likely to present cancer relapse, and/or that is likely to present a short overall survival (OS), event- free survival (EFS), metastasis-free survival (MFS), disease-free survival, short stable disease and/or short time to progression after anti-angiogenic treatment.
  • HCC hepatocellular carcinoma
  • the method of the invention in performed for predicting the overall survival (OS), progression- free survival (PFS) and/or the disease-free survival (DFS) of a subject afflicted with hepatocellular carcinoma (HCC) receiving anti-angiogenic treatment.
  • OS overall survival
  • PFS progression- free survival
  • DFS disease-free survival
  • the method of the present invention is particularly suitable for predicting the duration of the overall survival (OS), progression-free survival (PFS) and/or the disease-free survival (DFS) of a subject afflicted with hepatocellular carcinoma (HCC) receiving anti-angiogenic treatment.
  • OS survival time is generally based on and expressed as the percentage of people who survive a certain type of cancer for a specific amount of time.
  • OS rates do not specify whether cancer survivors are still undergoing treatment at five years or if they've become cancer-free (achieved remission).
  • DFS gives more specific information and is the number of people with a particular cancer who achieve remission.
  • progression-free survival (PFS) rates (the number of people who still have cancer, but their disease does not progress) includes people who may have had some success with treatment, but the cancer has not disappeared completely.
  • short survival time indicates that the subject will have a survival time that will be lower than the median (or mean) observed in the general population of patients suffering from said cancer.
  • long survival time indicates that the subject will have a survival time that will be higher than the median (or mean) observed in the general population of patients suffering from said cancer.
  • the subject will have a long survival time, it is meant that the subject will have a "good prognosis”.
  • Analyzing the expression level of the biomarker may be assessed by any of a wide variety of well-known methods for detecting expression of a transcribed nucleic acid or translated protein.
  • the expression level of the biomarker is assessed by analyzing the expression of the protein translated from said gene. Said analysis can be assessed using an antibody (e.g., a radio-labeled, chromophore- labeled, fluorophore-labeled, or enzyme-labeled antibody), an antibody derivative (e.g., an antibody conjugate with a substrate or with the protein or ligand of a protein of a protein/ligand pair (e.g., biotin-streptavidin)), or an antibody fragment (e.g., a single-chain antibody, an isolated antibody hypervariable domain, etc.) which binds specifically to the protein translated from the gene encoding for the biomarker.
  • an antibody e.g., a radio-labeled, chromophore- labeled, fluorophore-labeled, or enzyme-labeled antibody
  • an antibody derivative e.g., an antibody conjugate with a substrate or with the protein or ligand of
  • Methods for measuring the expression level of a biomarker in a sample may be assessed by any of a wide variety of well-known methods from one of skill in the art for detecting expression of a protein including, but not limited to, direct methods like mass spectrometry- based quantification methods, protein microarray methods, enzyme immunoassay (EIA), radioimmunoassay (RIA), Immunohistochemistry (IHC), Western blot analysis, ELISA, Luminex, ELISPOT and enzyme linked immunoabsorbant assay and indirects methods based on detecting expression of corresponding messenger ribonucleic acids (mRNAs).
  • the mRNA expression profile may be determined by any technology known by a man skilled in the art.
  • each mRNA expression level may be measured using any technology known by a man skilled in the art, including nucleic microarrays, quantitative Polymerase Chain Reaction (qPCR), next generation sequencing and hybridization with a labelled probe.
  • the binding partner may be an antibody that may be polyclonal or monoclonal, preferably monoclonal (e.g., a isotope-label, element-label, radio-labeled, chromophore- labeled, fluorophore-labeled, or enzyme-labeled antibody), an antibody derivative (e.g., an antibody conjugate with a substrate or with the protein or ligand of a protein of a protein/ligand pair (e.g., biotin-streptavidin)), or an antibody fragment (e.g., a single-chain antibody, an isolated antibody hypervariable domain, etc.) which binds specifically to the protein translated from the gene encoding for the biomarker of the invention.
  • the binding partner may be an aptamer.
  • the binding partners of the invention is an antibodies selected from the group consisting of but not limited to anti-human endocan/ESM-1 monoclonal antibody MEP08 (Bechard et al. (2000) J. Vase. Res. 37:417-425 ; Grigoriu et al. (2006) Clin. Cancer Res. 12:4575-4582 ; Maurage et al. (2009) Exp. Neurol. 68:836-844; Leroy et al. (2010) Histopathology 56: 180-187; Sarrazin et al. (2010) J. Cane. Sci. Ther. 2:47-52), anti-human endocan / ESM-1 antibody clone MEP19 (Bechard et al. (2000) J.
  • binding partners of the invention such as antibodies or aptamers, may be labelled with a detectable molecule or substance, such as an isotope, an element, a fluorescent molecule, a radioactive molecule or any others labels known in the art.
  • a detectable molecule or substance such as an isotope, an element, a fluorescent molecule, a radioactive molecule or any others labels known in the art.
  • Labels are known in the art that generally provide (either directly or indirectly) a signal.
  • the term "labelled", with regard to the antibody is intended to encompass direct labelling of the antibody or aptamer by coupling (i.e., physically linking) a detectable substance, such as an isotope, an element, a radioactive agent or a fluorophore (e.g. fluorescein isothiocyanate (FITC) or phycoerythrin (PE) or Indocyanine (Cy5)) to the antibody or aptamer, as well as indirect labelling of the probe or antibody by reactivity with a detectable substance.
  • a detectable substance such as an isotope, an element, a radioactive agent or a fluorophore (e.g. fluorescein isothiocyanate (FITC) or phycoerythrin (PE) or Indocyanine (Cy5)
  • FITC fluorescein isothiocyanate
  • PE phycoerythrin
  • Indocyanine Indocyanine
  • radioactive molecules include but are not limited to radioactive atom for scintigraphic studies such as 1123, 1124, Inl l l, Rel86, Rel88, specific isotopes include but are not limited to 13C, 15N, 1261, 79Br, 81 Br.
  • the afore mentioned assays generally involve the binding of the binding partner (ie. antibody or aptamer) to a solid support.
  • Solid supports which can be used in the practice of the invention include substrates such as nitrocellulose (e. g., in membrane or microtiter well form); polyvinylchloride (e. g., sheets or microtiter wells); polystyrene latex (e.g., beads or microtiter plates); polyvinylidene fluoride; diazotized paper; nylon membranes; activated beads, magnetically responsive beads, silicon wafers.
  • substrates such as nitrocellulose (e. g., in membrane or microtiter well form); polyvinylchloride (e. g., sheets or microtiter wells); polystyrene latex (e.g., beads or microtiter plates); polyvinylidene fluoride; diazotized paper; nylon membranes; activated beads, magnetically responsive beads, silicon wa
  • an ELISA method can be used, wherein the wells of a microtiter plate are coated with a set of antibodies which recognize said biomarker. A sample containing or suspected of containing said biomarker is then added to the coated wells. After a period of incubation sufficient to allow the formation of antibody-antigen complexes, the plate(s) can be washed to remove unbound moieties and a detectably labelled secondary binding molecule added. The secondary binding molecule is allowed to react with any captured sample marker protein, the plate washed and the presence of the secondary binding molecule detected using methods well known in the art such as Singulex, Quanterix, MSD, Bioscale, Cytof.
  • an Enzyme-linked immunospot (ELISpot) method may be used.
  • the sample is transferred to a plate which has been coated with the desired anti- biomarker capture antibodies.
  • Revelation is carried out with biotinylated secondary Abs and standard colorimetric or fluorimetric detection methods such as streptavidin-alkaline phosphatase and NBT-BCIP and the spots counted.
  • the bead may be a cytometric bead for use in flow cytometry.
  • Such beads may for example correspond to BDTM Cytometric Beads commercialized by BD Biosciences (San Jose, California).
  • cytometric beads may be suitable for preparing a multiplexed bead assay.
  • a multiplexed bead assay such as, for example, the BD(TM) Cytometric Bead Array, is a series of spectrally discrete beads that can be used to capture and quantify soluble antigens.
  • beads are labelled with one or more spectrally distinct fluorescent dyes, and detection is carried out using a multiplicity of photodetectors, one for each distinct dye to be detected.
  • a number of methods of making and using sets of distinguishable beads have been described in the literature. These include beads distinguishable by size, wherein each size bead is coated with a different target-specific antibody (see e.g. Fulwyler and McHugh, 1990, Methods in Cell Biology 33:613-629), beads with two or more fluorescent dyes at varying concentrations, wherein the beads are identified by the levels of fluorescence dyes (see e.g. European Patent No.
  • beads distinguishably labelled with two different dyes, wherein the beads are identified by separately measuring the fluorescence intensity of each of the dyes (see e.g. U.S. patent Nos. 4,499,052 and 4,717,655).
  • Both one-dimensional and two-dimensional arrays for the simultaneous analysis of multiple antigens by flow cytometry are available commercially. Examples of one-dimensional arrays of singly dyed beads distinguishable by the level of fluorescence intensity include the BD(TM) Cytometric Bead Array (CBA) (BD Biosciences, San Jose, Calif.) and Cyto-Plex(TM) Flow Cytometry microspheres (Duke Scientific, Palo Alto, Calif).
  • An example of a two-dimensional array of beads distinguishable by a combination of fluorescence intensity (five levels) and size (two sizes) is the QuantumPlex(TM) microspheres (Bangs Laboratories, Fisher, Ind.).
  • An example of a two-dimensional array of doubly-dyed beads distinguishable by the levels of fluorescence of each of the two dyes is described in Fulton et al. (1997, Clinical Chemistry 43(9): 1749-1756).
  • the beads may be labelled with any fluorescent compound known in the art such as e.g. FITC (FL1), PE (FL2), fluorophores for use in the blue laser (e.g.
  • bead is a magnetic bead for use in magnetic separation. Magnetic beads are known to those of skill in the art. Typically, the magnetic bead is preferably made of a magnetic material selected from the group consisting of metals (e.g. ferrum, cobalt and nickel), an alloy thereof and an oxide thereof. In another particular embodiment, bead is bead that is dyed and magnetized.
  • metals e.g. ferrum, cobalt and nickel
  • bead is bead that is dyed and magnetized.
  • protein microarray methods may be used.
  • at least one antibody or aptamer directed against the biomarker is immobilized or grafted to an array(s), a solid or semi-solid surface(s).
  • a sample containing or suspected of containing the biomarker is then labelled with at least one isotope or one element or one fluorophore or one colorimetric tag that are not naturally contained in the tested sample.
  • the array is then washed and dried.
  • quantifying said biomarker may be achieved using any appropriate microarray scanner like fluorescence scanner, colorimetric scanner, SIMS (secondary ions mass spectrometry) scanner, maldi scanner, electromagnetic scanner or any technique allowing to quantify said labels.
  • the antibody or aptamer grafted on the array is labelled.
  • reverse phase arrays may be used.
  • at least one sample is immobilized or grafted to an array(s), a solid or semi-solid surface(s).
  • An antibody or aptamer against the suspected biomarker is then labelled with at least one isotope or one element or one fluorophore or one colorimetric tag that are not naturally contained in the tested sample.
  • the array is then washed and dried.
  • detecting quantifying and counting by D-SIMS said biomarker containing said isotope or group of isotopes, and a reference natural element, and then calculating the isotopic ratio between the biomarker and the reference natural element may be achieve using any appropriate microarray scanner like fluorescence scanner, colorimetric scanner, SIMS (secondary ions mass spectrometry) scanner, maldi scanner, electromagnetic scanner or any technique allowing to quantify said labels.
  • said direct analysis can also be assessed by mass Spectrometry.
  • Mass spectrometry-based quantification methods may be performed using either labelled or unlabelled approaches (DeSouza and Siu, 2012).
  • Mass spectrometry-based quantification methods may be performed using chemical labeling, metabolic labelingor proteolytic labeling. Mass spectrometry-based quantification methods may be performed using mass spectrometry label free quantification, LTQ Orbitrap Velos, LTQ-MS/MS, a quantification based on extracted ion chromatogram EIC (progenesis LC-MS, Liquid chromatography-mass spectrometry) and then profile alignement to determine differential expression of biomarker.
  • EIC protogenesis LC-MS, Liquid chromatography-mass spectrometry
  • the expression level of the biomarker is assessed by analyzing the expression of mRNA transcript or mRNA precursors, such as nascent RNA, of biomarker gene. Said analysis can be assessed by preparing mRNA/cDNA from cells in a sample from a subject, and hybridizing the mRNA/cDNA with a reference polynucleotide. The prepared mRNA/cDNA can be used in hybridization or amplification assays that include, but are not limited to, Southern or Northern analyses, polymerase chain reaction analyses, such as quantitative PCR (TaqMan), and probes arrays such as GeneChip(TM) DNA Arrays (AFFYMETRIX).
  • mRNA transcript or mRNA precursors such as nascent RNA
  • the analysis of the expression level of mRNA transcribed from the gene encoding for biomarker involves the process of nucleic acid amplification, e. g., by RT- PCR (the experimental embodiment set forth in U. S. Patent No. 4,683, 202), ligase chain reaction (Barany, 1991), self sustained sequence replication (Guatelli et al, 1990), transcriptional amplification system (Kwoh et al., 1989), Q-Beta Replicase (Lizardi et al., 1988), rolling circle replication (U. S. Patent No. 5,854, 033) or any other nucleic acid amplification method, followed by the detection of the amplified molecules using techniques well known to those of skill in the art.
  • RT- PCR the experimental embodiment set forth in U. S. Patent No. 4,683, 202
  • ligase chain reaction Barany, 1991
  • self sustained sequence replication (Guatelli et al, 1990)
  • transcriptional amplification system Kwoh e
  • amplification primers are defined as being a pair of nucleic acid molecules that can anneal to 5' or 3' regions of a gene (plus and minus strands, respectively, or vice-versa) and contain a short region in between.
  • amplification primers are from about 10 to 30 nucleotides in length and flank a region from about 50 to 200 nucleotides in length. Under appropriate conditions and with appropriate reagents, such primers permit the amplification of a nucleic acid molecule comprising the nucleotide sequence flanked by the primers.
  • the invention also relates to a kit for performing the methods as above described, wherein said kit comprises means for measuring the expression level of endocan that is indicative of subject responder to anti-angiogenic treatment.
  • the kit may include an antibody, a set of antibodies, primers, or probes as above described.
  • the antibody or set of antibodies are labelled as above described.
  • the kit may also contain other suitably packaged reagents and materials needed for the particular detection protocol, including solid-phase matrices, if applicable, and standards.
  • the method of the invention allows to define a subgroup of subjects who will be responder or non responder to anti-angiogenic treatment.
  • a further aspect of the invention relates to a method for treating hepatocellular carcinoma in a subject in need thereof comprising the steps of:
  • ESMl immunoreactivity is semi-quantitatively evaluated in human HCC tissue according to Ziol et al (J Hepatol 2013; 59: 1264-1270). In detail, cases showing at least two intratumoral endothelial immunoreactive cells (IRC; cytoplasmic staining) to ESMl in a high power field (HPF, 40x) are considered as positive.
  • IRC intratumoral endothelial immunoreactive cells
  • HPF, 40x high power field
  • ESMl immunoreactivity was evaluated in two series of cases: 1) HCC removed surgically and 2) HCC treated with Sorafenib; both with known clinical and pathological information.
  • ESM1 score cut-off For each series we examined different ESM1 score thresholds and compared them to clinical and pathological data; based upon these preliminary experimental data we arbitrarily defined a cut-off value of ESM score which optimized the benefit/risk balance (clinical consequences of false positive and false negative).
  • ESM1 score semiquantitatively measures ESM1 protein expression (Endocan) in human HCC. It is obtained by counting ESM1 immunoreactive cells in 10 adjacent HPF and then calculated with the following formula: (1 x mP HPF) + (2 x MP HPF). [mP: minor positivity; MP: major positivity]
  • Biopsy material is frequently small and fragmented with less than 10 HPF.
  • ESM1 scoreor biopsy material is counted with the following formula: 10 x ESM score /n° of counted HPF.
  • Example: in a case where only 5 HPF can be counted and show 2 negative HPF and 3 mP HPF, the ESM score is the following: 10 x (1x4) / 5 8.
  • Cut-off value of ESM1 score It is the value experimentally set at a threshold of 5 above which predicting HCC patients who will benefit from sorafenib treatment.

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Abstract

La présente invention concerne des procédés de prédiction de la réponse thérapeutique dans le cancer hépatocellulaire. Les inventeurs ont étudié le rôle de marqueurs vasculaires, notamment l'endocan, dans la prédiction du devenir de l'hépatocarcinogenèse et d'un carcinome hépatocellulaire (HCC) après traitement. Les inventeurs ont démontré qu'une coloration par encodan permet de prédire une survie sans récidive plus faible pour le HCC réséqué et une maladie stable plus longue après traitement par sorafénib. Ainsi, l'invention concerne un procédé permettant de déterminer si un sujet atteint d'un carcinome hépatocellulaire (HCC) répondra ou non à un traitement anti-angiogénique tel que par sorafénib, comprenant l'étape consistant à mesurer le taux d'expression de l'endocan dans un échantillon biologique issu dudit sujet.
PCT/EP2018/077554 2017-10-11 2018-10-10 Méthodes de prédiction de la réponse thérapeutique dans le cancer hépatocellulaire Ceased WO2019072888A1 (fr)

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Publication number Priority date Publication date Assignee Title
CN112098536A (zh) * 2020-08-19 2020-12-18 四川省肿瘤医院 一种测定人血浆中舒尼替尼浓度的方法

Citations (30)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0126450A2 (fr) 1983-05-19 1984-11-28 Ioannis Dr. Tripatzis Particule et méthode de détection d'antigènes et/ou anticorps utilisant cette particule
US4499052A (en) 1982-08-30 1985-02-12 Becton, Dickinson And Company Apparatus for distinguishing multiple subpopulations of cells
US4683202A (en) 1985-03-28 1987-07-28 Cetus Corporation Process for amplifying nucleic acid sequences
US4717655A (en) 1982-08-30 1988-01-05 Becton, Dickinson And Company Method and apparatus for distinguishing multiple subpopulations of cells
US5618829A (en) 1993-01-28 1997-04-08 Mitsubishi Chemical Corporation Tyrosine kinase inhibitors and benzoylacrylamide derivatives
US5639757A (en) 1995-05-23 1997-06-17 Pfizer Inc. 4-aminopyrrolo[2,3-d]pyrimidines as tyrosine kinase inhibitors
US5728868A (en) 1993-07-15 1998-03-17 Cancer Research Campaign Technology Limited Prodrugs of protein tyrosine kinase inhibitors
US5804396A (en) 1994-10-12 1998-09-08 Sugen, Inc. Assay for agents active in proliferative disorders
US5854033A (en) 1995-11-21 1998-12-29 Yale University Rolling circle replication reporter systems
US6100254A (en) 1997-10-10 2000-08-08 Board Of Regents, The University Of Texas System Inhibitors of protein tyrosine kinases
US6127374A (en) 1997-07-29 2000-10-03 Warner-Lambert Company Irreversible inhibitors of tyrosine kinases
US6245759B1 (en) 1999-03-11 2001-06-12 Merck & Co., Inc. Tyrosine kinase inhibitors
US6306874B1 (en) 1999-10-19 2001-10-23 Merck & Co., Inc. Tyrosine kinase inhibitors
US6313138B1 (en) 2000-02-25 2001-11-06 Merck & Co., Inc. Tyrosine kinase inhibitors
US6316444B1 (en) 1999-06-30 2001-11-13 Merck & Co., Inc. SRC kinase inhibitor compounds
US6329380B1 (en) 1999-06-30 2001-12-11 Merck & Co., Inc. SRC kinase inhibitor compounds
US6344459B1 (en) 1996-04-12 2002-02-05 Warner-Lambert Company Irreversible inhibitors of tyrosine kinases
US6420382B2 (en) 2000-02-25 2002-07-16 Merck & Co., Inc. Tyrosine kinase inhibitors
US6479512B1 (en) 1999-10-19 2002-11-12 Merck & Co., Inc. Tyrosine kinase inhibitors
US6498165B1 (en) 1999-06-30 2002-12-24 Merck & Co., Inc. Src kinase inhibitor compounds
US6586423B2 (en) 1999-09-10 2003-07-01 Merck & Co., Inc. Tyrosine kinase inhibitors
US6740665B1 (en) 1999-02-10 2004-05-25 Ramachandran Murali Tyrosine kinase inhibitors and methods of using the same
US6794393B1 (en) 1999-10-19 2004-09-21 Merck & Co., Inc. Tyrosine kinase inhibitors
US6875767B2 (en) 2001-06-22 2005-04-05 Merck & Co., Inc. (5-cyano-2-thiazolyl)amino-4-pyridine tyrosine kinase inhibitors
US6927293B2 (en) 2001-08-30 2005-08-09 Merck & Co., Inc. Tyrosine kinase inhibitors
US6958340B2 (en) 2001-08-01 2005-10-25 Merck & Co., Inc. Tyrosine kinase inhibitors
US7235576B1 (en) 2001-01-12 2007-06-26 Bayer Pharmaceuticals Corporation Omega-carboxyaryl substituted diphenyl ureas as raf kinase inhibitors
US20070254295A1 (en) 2006-03-17 2007-11-01 Prometheus Laboratories Inc. Methods of predicting and monitoring tyrosine kinase inhibitor therapy
US20090192200A1 (en) 2008-01-17 2009-07-30 Ales Gavenda Polymorphs of sorafenib tosylate and sorafenib hemi-tosylate, and processes for preparation thereof
EP2706358A2 (fr) * 2008-12-23 2014-03-12 Merck Patent GmbH Biomarqueurs pour inhibiteurs présentant une activité anti-angiogénique

Patent Citations (34)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4499052A (en) 1982-08-30 1985-02-12 Becton, Dickinson And Company Apparatus for distinguishing multiple subpopulations of cells
US4717655A (en) 1982-08-30 1988-01-05 Becton, Dickinson And Company Method and apparatus for distinguishing multiple subpopulations of cells
EP0126450A2 (fr) 1983-05-19 1984-11-28 Ioannis Dr. Tripatzis Particule et méthode de détection d'antigènes et/ou anticorps utilisant cette particule
US4683202A (en) 1985-03-28 1987-07-28 Cetus Corporation Process for amplifying nucleic acid sequences
US4683202B1 (fr) 1985-03-28 1990-11-27 Cetus Corp
US5618829A (en) 1993-01-28 1997-04-08 Mitsubishi Chemical Corporation Tyrosine kinase inhibitors and benzoylacrylamide derivatives
US5728868A (en) 1993-07-15 1998-03-17 Cancer Research Campaign Technology Limited Prodrugs of protein tyrosine kinase inhibitors
US5804396A (en) 1994-10-12 1998-09-08 Sugen, Inc. Assay for agents active in proliferative disorders
US5639757A (en) 1995-05-23 1997-06-17 Pfizer Inc. 4-aminopyrrolo[2,3-d]pyrimidines as tyrosine kinase inhibitors
US5854033A (en) 1995-11-21 1998-12-29 Yale University Rolling circle replication reporter systems
US6344459B1 (en) 1996-04-12 2002-02-05 Warner-Lambert Company Irreversible inhibitors of tyrosine kinases
US6127374A (en) 1997-07-29 2000-10-03 Warner-Lambert Company Irreversible inhibitors of tyrosine kinases
US6562818B1 (en) 1997-07-29 2003-05-13 Warner-Lambert Company Irreversible inhibitors of tyrosine kinases
US6100254A (en) 1997-10-10 2000-08-08 Board Of Regents, The University Of Texas System Inhibitors of protein tyrosine kinases
US6740665B1 (en) 1999-02-10 2004-05-25 Ramachandran Murali Tyrosine kinase inhibitors and methods of using the same
US6245759B1 (en) 1999-03-11 2001-06-12 Merck & Co., Inc. Tyrosine kinase inhibitors
US6544988B1 (en) 1999-03-11 2003-04-08 Merck & Co., Inc. Tyrosine kinase inhibitors
US6329380B1 (en) 1999-06-30 2001-12-11 Merck & Co., Inc. SRC kinase inhibitor compounds
US6498165B1 (en) 1999-06-30 2002-12-24 Merck & Co., Inc. Src kinase inhibitor compounds
US6316444B1 (en) 1999-06-30 2001-11-13 Merck & Co., Inc. SRC kinase inhibitor compounds
US6586423B2 (en) 1999-09-10 2003-07-01 Merck & Co., Inc. Tyrosine kinase inhibitors
US6586424B2 (en) 1999-09-10 2003-07-01 Merck & Co., Inc. Tyrosine kinase inhibitors
US6306874B1 (en) 1999-10-19 2001-10-23 Merck & Co., Inc. Tyrosine kinase inhibitors
US6479512B1 (en) 1999-10-19 2002-11-12 Merck & Co., Inc. Tyrosine kinase inhibitors
US6794393B1 (en) 1999-10-19 2004-09-21 Merck & Co., Inc. Tyrosine kinase inhibitors
US6313138B1 (en) 2000-02-25 2001-11-06 Merck & Co., Inc. Tyrosine kinase inhibitors
US6420382B2 (en) 2000-02-25 2002-07-16 Merck & Co., Inc. Tyrosine kinase inhibitors
US7235576B1 (en) 2001-01-12 2007-06-26 Bayer Pharmaceuticals Corporation Omega-carboxyaryl substituted diphenyl ureas as raf kinase inhibitors
US6875767B2 (en) 2001-06-22 2005-04-05 Merck & Co., Inc. (5-cyano-2-thiazolyl)amino-4-pyridine tyrosine kinase inhibitors
US6958340B2 (en) 2001-08-01 2005-10-25 Merck & Co., Inc. Tyrosine kinase inhibitors
US6927293B2 (en) 2001-08-30 2005-08-09 Merck & Co., Inc. Tyrosine kinase inhibitors
US20070254295A1 (en) 2006-03-17 2007-11-01 Prometheus Laboratories Inc. Methods of predicting and monitoring tyrosine kinase inhibitor therapy
US20090192200A1 (en) 2008-01-17 2009-07-30 Ales Gavenda Polymorphs of sorafenib tosylate and sorafenib hemi-tosylate, and processes for preparation thereof
EP2706358A2 (fr) * 2008-12-23 2014-03-12 Merck Patent GmbH Biomarqueurs pour inhibiteurs présentant une activité anti-angiogénique

Non-Patent Citations (11)

* Cited by examiner, † Cited by third party
Title
BECHARD ET AL., J. VASE. RES., vol. 37, 2000, pages 417 - 425
CHEMICAL ABSTRACTS, Columbus, Ohio, US; abstract no. 284461-73-0
FULTON ET AL., CLINICAL CHEMISTRY, vol. 43, no. 9, 1997, pages 1749 - 1756
FULWYLER; MCHUGH, METHODS IN CELL BIOLOGY, vol. 33, 1990, pages 613 - 629
GRIGORIU ET AL., CLIN. CANCER RES., vol. 12, 2006, pages 4575 - 4582
J.-C. NAULT ET AL: "Serum Proteoglycans as Prognostic Biomarkers of Hepatocellular Carcinoma in Patients with Alcoholic Cirrhosis", CANCER EPIDEMIOLOGY, BIOMARKERS AND PREVENTION., vol. 22, no. 8, 18 June 2013 (2013-06-18), US, pages 1343 - 1352, XP055453452, ISSN: 1055-9965, DOI: 10.1158/1055-9965.EPI-13-0179 *
LEROY ET AL., HISTOPATHOLOGY, vol. 56, 2010, pages 180 - 187
MAURAGE ET AL., EXP. NEUROL., vol. 68, 2009, pages 836 - 844
SARRAZIN ET AL., GLYCOBIOLOGY, vol. 20, 2010, pages 1380 - 1388
SARRAZIN ET AL., J. CANC. SCI. THER., vol. 2, 2010, pages 47 - 52
ZIOL ET AL., J HEPATOL, vol. 59, 2013, pages 1264 - 1270

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN112098536A (zh) * 2020-08-19 2020-12-18 四川省肿瘤医院 一种测定人血浆中舒尼替尼浓度的方法

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