WO2021175863A1 - Method for diagnosis and/or prognosis of liver disease progression and risk of hepatocellular carcinoma and discovery of therapeutic compounds and targets to treat liver disease and cancer - Google Patents

Method for diagnosis and/or prognosis of liver disease progression and risk of hepatocellular carcinoma and discovery of therapeutic compounds and targets to treat liver disease and cancer Download PDF

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Publication number
WO2021175863A1
WO2021175863A1 PCT/EP2021/055203 EP2021055203W WO2021175863A1 WO 2021175863 A1 WO2021175863 A1 WO 2021175863A1 EP 2021055203 W EP2021055203 W EP 2021055203W WO 2021175863 A1 WO2021175863 A1 WO 2021175863A1
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WIPO (PCT)
Prior art keywords
liver disease
liver
risk
marker
subject
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PCT/EP2021/055203
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French (fr)
Inventor
Thomas Baumert
Joachim Lupberger
Frank Sven JÜHLING
Yujin Hoshida
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Université De Strasbourg
Institut National De La Sante Et De La Recherche Medicale (Inserm)
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Priority to US202062983965P priority Critical
Priority to US62/983,965 priority
Application filed by Université De Strasbourg, Institut National De La Sante Et De La Recherche Medicale (Inserm) filed Critical Université De Strasbourg
Publication of WO2021175863A1 publication Critical patent/WO2021175863A1/en

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    • GPHYSICS
    • G01MEASURING; TESTING
    • G01NINVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/53Immunoassay; Biospecific binding assay; Materials therefor
    • G01N33/574Immunoassay; Biospecific binding assay; Materials therefor for cancer
    • G01N33/57407Specifically defined cancers
    • G01N33/57438Specifically defined cancers of liver, pancreas or kidney
    • GPHYSICS
    • G01MEASURING; TESTING
    • G01NINVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/5005Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells
    • G01N33/5008Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells for testing or evaluating the effect of chemical or biological compounds, e.g. drugs, cosmetics
    • G01N33/5044Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells for testing or evaluating the effect of chemical or biological compounds, e.g. drugs, cosmetics involving specific cell types
    • G01N33/5067Liver cells
    • GPHYSICS
    • G01MEASURING; TESTING
    • G01NINVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2800/00Detection or diagnosis of diseases
    • G01N2800/08Hepato-biliairy disorders other than hepatitis
    • G01N2800/085Liver diseases, e.g. portal hypertension, fibrosis, cirrhosis, bilirubin
    • GPHYSICS
    • G01MEASURING; TESTING
    • G01NINVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2800/00Detection or diagnosis of diseases
    • G01N2800/52Predicting or monitoring the response to treatment, e.g. for selection of therapy based on assay results in personalised medicine; Prognosis

Abstract

The present invention relates to diagnosis and/or prognosis of liver disease progression and risk of hepatocellular carcinoma and the discovery of therapeutic compounds and targets to treat liver disease and cancer.

Description

Method for diagnosis and/or prognosis of liver disease progression and risk of hepatocellular carcinoma and discovery of therapeutic compounds and targets to treat liver disease and cancer
FIELD OF THE INVENTION
The present invention relates to diagnosis and/or prognosis of liver disease progression and risk of hepatocellular carcinoma and the discovery of therapeutic compounds and targets to treat liver disease and cancer.
BACKGROUND OF THE INVENTION
Hepatocellular carcinoma (HCC) is the most common primary malignancy of the liver with rising incidence[l]. HCC usually arises in advanced liver disease of viral and metabolic origin. Chronic hepatitis C (CHC) is a major cause of HCC. The HCC risk still remains elevated post-cure especially in patients with advanced fibrosis [2]. Non-alcoholic steatohepatitis (NASH) patients are also at high risk of developing HCC. Given the change in lifestyle with increasing obesity and diabetes, NASH will replace viral hepatitis as major cause for HCC[3]. Liver fibrosis is the key risk factor of HCC and HCC almost arises in advanced liver fibrosis [4]. There are no approved therapeutic strategies to treat liver fibrosis and prevent liver disease progression to HCC [4]. Due to the high HCC mortality and unsatisfactory treatment options, the development of strategies to treat liver fibrosis and prevent liver disease progression to HCC is a key unmet medical need[4].
Epigenetic regulation is a major determinant of gene expression. Alteration of the epigenetic program plays a key role for pathogenesis of human disease and cancer[5]. Several studies have investigated the role of epigenetics in HCC, however the role of epigenome modifications for liver disease progression and hepatocarcinogenesis is only recently emerging. The inventors and others have recently demonstrated that CHC results in genome-wide epigenetic modifications, which are associated with HCC risk and persist post cure with DAA[6, 7]
The reversibility of epigenetic changes offers a therapeutic perspective to counteract the associated transcriptional changes and their functional consequences for disease biology. Small molecule inhibitors targeting chromatin modifiers or readers are currently explored as therapeutic approaches with a particular focus on cancer[8, 9]. Thus, there is a pressing need of new therapy to treat liver disease and prevent liver disease progression and the development of hepatocellular carcinoma. To identify patients at risk for liver disease progression and HCC, it is important to identify epigenetic and transcriptional changes associated with HCC in CHC and NASH patient and assess their impact as biomarker for surveillance and treatment approaches. The identification of pathways associated with liver disease progression and hepatocarcinogenesis provides opportunities to treat advanced liver disease and prevent HCC.
SUMMARY OF THE INVENTION
The present invention features, at least in part, a method of diagnosis and/or prognosis of liver disease progression and risk of hepatocellular carcinoma in a subject comprising detection of an epigenetic or transcriptomic change in subjects with liver disease, the method comprising comparing the level of expression of a marker or a plurality of markers in a subject sample; and the level of expression of the marker or plurality of markers in a control sample, wherein the marker or plurality of markers are selected from the group consisting of the markers listed in table S3 and a significant difference between the level of expression of the marker or plurality of markers in the subject sample and the control sample is an indication that the subject is at risk for progression of liver disease and developing a hepatocellular carcinoma. In one embodiment, the subject is at risk for progression of liver disease, death and developing a hepatocellular carcinoma and the liver disease is a non-alcoholic or alcoholic steatohepatitis or chronic hepatitis A, B, C, D, E -related liver disease or liver fibrosis. In another embodiment, the liver disease is a non-alcoholic or alcoholic steatohepatitis or chronic hepatitis B or C-related liver disease or liver fibrosis. In another embodiment, the subject is a direct- acting antivirals- cured patient or a patient cured of viral infection by any treatment.
In one embodiment the marker or plurality of markers have increased expression relative to a control. In another embodiment the marker or plurality of markers have decreased expression relative to a control. In another embodiment, at least one marker has increased expression and at least one marker has decreased expression relative to a control. The marker can be detected in liver tissue, the serum or plasma or urine or any other body part.
In one embodiment, the subject has undergone tumor resection and in another embodiment the subject sample is obtained from non-tumorous liver tissue or tissue surrounding a resected tumor. In another embodiment, the patient has undergone liver biopsy of fine needle aspiration or obtained a blood test. In yet another embodiment the subject sample is selected from the group consisting of fresh tissue, fresh frozen tissue, fixed embedded tissue or subject-derived spheroids. In still another embodiment, the subject-derived spheroids were generated from fresh liver tissue and cultured in spheroid culture medium. In another embodiment, the subject sample is serum or plasma or urine.
The present invention also features a method of diagnosis and/or prognosis of liver disease progression, survival or risk hepatocellular carcinoma in a subject comprising detecting a biomarker selected from the list of 1693 genes displayed in Table S3.
The present invention also features a method of diagnosis and/or prognosis of liver disease progression, survival or risk hepatocellular carcinoma in a subject comprising detecting a biomarker selected from GPRIN3, COL1A2, SLC7A6, CHST11, LBH, TRPC1, IGF2BP2, ARRDC2, SELM, TMED3, GSTA1, GRB14, SERPINA5, CAT, SLC25A1, PKLR, ADH4, GLYAT, TTR, HPX, RARRES2, ACADSB, CFHR5, DCXR, and GALK1 genes.
The present invention further features a method of assessing the efficacy of a liver disease and hepatocellular carcinoma prevention and treatment approach in a subject with liver disease, the method comprising comparing the level of expression of a marker or a plurality of markers in a subject sample; and the level of expression of the marker or plurality of markers in a second subject sample following the treatment with the therapy, wherein the marker or plurality of markers are selected from the group consisting of the markers listed in Table S3, and a significant difference between the level of expression of the marker or plurality of markers indicates the efficacy of the liver disease or hepatocellular carcinoma prevention therapy.
The present invention further features a method of identifying an agent or compound for use in treatment of viral and metabolic liver disease and chemoprevention or treatment of metabolic and viral hepatocellular carcinoma, said method comprising the steps of providing a sample, contacting the sample with a candidate compound; and detecting an increase or decrease in expression of a marker or a plurality of markers selected from the group consisting of the markers in Table S3, relative to a control, wherein an agent or compound that increases or decreases the expression of said marker or plurality of markers relative to the control is an agent or compound for use in treatment of liver disease or chemoprevention or treatment of metabolic and viral hepatocellular carcinoma. In one embodiment the sample is a subject- derived HCC or adjacent liver tissues or a cancer cell line. In another embodiment the liver cancer cell line is selected from the group consisting of the Huh6, Huh7, Huh7.5.1, Hep3B.l- 7, HepG2, SkHepI, C3A, PLC/PRF/5 and SNU-398 cell lines or optionally a combination with another cell line such as LX2 cells, THP1 cells or another cell line or primary cells such as human Kupffer cells or human myofibroblasts or liver sinusoidal endothelial cell