How Will New Therapies Affect HCC Development? July 6, 2018 Scott Friedman, M.D. Fishberg Professor of Medicine Dean for Therapeutic Discovery Chief, Division of Liver Diseases Icahn School of Medicine at Mount Sinai
Rising Contribution of NAFLD to HCC in Newcastle, UK - NAFLD accounted for 34.8% of HCC - 30% did not have cirrhosis - If PNPLA3 polymorphism present, OR=12.9 Dyson et al, Journal of Hepatology, Volume 60, 110 117, 2014
NASH is the Fastest Growing Cause of HCC Among Liver Diseases NASH Younossi et al, J Clin Gastro Hep, 2018, in press.
Mechanisms of Increased Cancer Risk Associated with Obesity Obesity confers increased risk of all cancers, but esp. HCC A chronic inflammatory state, with more oxidant stress, DNA damage and mutations Increased estrogen production by fat Higher circulating IGF and insulin Increased adipokines, especially leptin, which is a mitogen Altered gut microbiome
Genomic Features of HCC in NASH Very few studies; too early to draw conclusions Pathways regulated by HNF4 reported in one study (Frades, PLoS one, 2015) Prognostic signatures reported (Frades, PLoS one, 2015) May have unique epigenetic features (Deconti, Mol Canc Res, 2017; Dechass, Mol Carcinogenesis, 2018)
% of mice % of mice HCC Development in Western Diet/CCl 4 NASH Model A B D E F High fat, high cholesterol, high fructose diet with weekly CCl 4 IP Tumor numbers per mouse H I Largest tumor J size 100 None < 5 6 to 10 > 10 50 100 50 None 1-5 mm 6-10 mm 0 ND/Oil WD/Oil ND/CCl4 WD/CCl4 0 ND/Oil WD/Oil ND/CCl4 WD/CCl4 Tsuchida et al, J Hepatol in press
Using Big Data Approaches to Identify Disease-relevant Pathways Comparison of Animal Models and Human NAFLD 0.001 Averaged p-values of two human cohorts 1.0 0.001 NASH vs. healthy liver Advanced vs. mild NASH WD + CCl 4 12w WD 12w WD 24w WD + CCl 4 24w HFChSuD #1 HFChSuD #2 C3H/HeJ + CFD STAM CCl 4 12w CCl 4 24w A/J + CFD HFChD #1 WSB/EiJ + CFD HFChD #2 HFChSuD #3 Mir122 KO Gnmt KO Pten KO HFD MCD + HFD Mat1a KO ob/ob KEGG Diet duration 20 weeks < 20 weeks Mouse model type Diet duration Model type Obesity Insulin resistance Fibrosis Ballooning Inflammation HCC Diet Diet + chemical Similarity to NASH (vs. healthy liver) Similarity to advanced (vs. mild) NASH Phenotype Genetic Chemica l Presence Absence n. a. FOCAL ADHESION SMALL CELL LUNG CANCER ECM RECEPTOR INTERACTION VIRAL MYOCARDITIS LEUKOCYTE TRANSENDOTHELIAL MIGRATION ALLOGRAFT REJECTION INTESTINAL IMMUNE NETWORK FOR IGA PRODUCTION CELL ADHESION MOLECULES CAMS CHEMOKINE SIGNALING PATHWAY ARRHYTHMOGENIC RIGHT VETRICULAR CARDIOMYOPATHY ARVC TYPE I DIABETES MELLITUS PRIMARY IMMUNODEFICIENCY HEMATOPOIETIC CELL LINEAGE FC GAMMA R MEDIATED PHAGOCYTOSIS FC EPSILON RI SIGNALING PATHWAY TOLL LIKE RECEPTOR SIGNALING PATHWAY LEISHMANIA INFECTION AUTOIMMUNE THYROID DISEASE ASTHMA NATURAL KILLER CELL MEDIATED CYTOTOXICITY B CELL RECEPTOR SIGNALING PATHWAY PANCREATIC CANCER ANTIGEN PROCESSING AND PRESENTATION PPAR SIGNALING PATHWAY T CELL RECEPTOR SIGNALING PATHWAY SYSTEMIC LUPUS ERYTHEMATOSUS GRAFT VERSUS HOST DISEASE PROPANOATE METABOLSIM LYSINE DEGRADATION VALINE LEUCINE AND ISOLEUCINE DEGRADATION FATTY ACID METABOLISM PEROXISOME TRYPTOPHAN METABOLISM RIBOSOME GLYCINE SERINE AND THREONINE METABOLISM Similarity to NASH (vs. healthy liver) Similarity to advanced (vs. mild) NASH Euclidean distance Molecular pathway modulation (gene set enrichment p-value) Mi n Similar Max Dissimilar 0.001 1.0 Suppression Induction 0.001 Tsuchida et al, J Hepatol in press
Links from NASH to HCC STEATOHEPATITIS Impaired autophagy in hepatocytes Microbiome effects Zhang & Friedman. Hepatology 2015
Ngee Kiat Chua et al., Sci Transl Med 2018;10:eaat3741 Squalene Epoxide Drives NAFLD-HCC
Links from NASH to HCC STEATOHEPATITIS Impaired Impaired autophagy autophagy in in hepatocytes hepatocytes Altered lymphocyte fxn Microbiome effects Zhang & Friedman. Hepatology 2015
Links from NASH to HCC STEATOHEPATITIS Impaired autophagy in hepatocytes Altered lymphocyte fxn Microbiome effects Zhang & Friedman. Hepatology 2015
Autophagy A highly conserved cellular pathway to preserve energy homeostasis through degradation of intracellular substrates Choi et al, 2013 NEJM
Czaja, Dig Dis Sci, 2016 Autophagy is Defective in NAFLD
Autophagy-defective mice develop HCC Mice with hepatocyte-specific deletion of Atg7, a key autophagy effector 100% Penetrance Reticulin staining in normal liver ST Atg7 KO Tumor Multinodular HCC with loss of reticulin Youngmin Lee
Atg7 KO mice Display Varying HCC subtypes Also CCC-like (not shown) Mesenchymal like (not shown) Youngmin Lee
Links from NASH to HCC STEATOHEPATITIS Impaired autophagy in hepatocytes Altered lymphocyte fxn Microbiome effects Zhang & Friedman. Hepatology 2015
NAFLD Induces a Selective Loss of Intrahepatic CD4 + T lymphocytes and Promotes HCC C Ma et al. Nature 1 5 (2016) doi:10.1038/nature16969
Links from NASH to HCC STEATOHEPATITIS Impaired autophagy in hepatocytes Altered lymphocyte fxn Microbiome effects Zhang & Friedman. Hepatology 2015
Gut Microbiome Modulates Liver Cancer through Bile acid regulated NKT cells Chi Ma et al. Science 2018;360:eaan5931
Links from NASH to HCC STEATOHEPATITIS Impaired autophagy in hepatocytes Microbiome effects Zhang & Friedman. Hepatology 2015
Hepatic Stellate cell Activation - A Central Event in Liver Fibrosis Normal Liver Activated HSC with Fibrosis Friedman SL and Arthur, Science and Medicine, 2002
Activation of HSCs is Associated with Loss of Retinyl Ester Droplets INJURY Autophagy PDGF Friedman SL, J Biol Chem, 2000; Hernandez-Gea, Gastroenterology 2015 Retinoid Loss
Pancreatic Stellate Cells feed a Tumor through Autophagy-Regulated Alanine Secretion Kamphorst and Gottlieb based on Sousa et al, Nature 536, 479 483, 2016
Hepatic Drivers of Fibrosis in NASH Adipokine dysregulation Cannabinoids Insulin / IGF1 ER Stress Steatotic hepatocyte Chemokines Innate immune signaling Inflammasome activation Free Cholesterol Lipotoxicity Indian hedgehog Osteopontin J Gregory 2016 Mount Sinai Health System Activated stellate cell Epigenetic changes Yap / Hippo Cannabinoids ER stress
Liver-Related NASH Targets in Phase 2 and 3 Trials FXR ACC 1 / 2 FGF19 /21 PPAR a, g, d SCD1 THRb Niacin R SIRT1 Ketohexokinase PPAR g, GLP1 & GLP1R SGLT2 Steatotic hepatocyte mtot Caspases Oxidant stress CCR2 / 5 ASK-1 5-lipooxygenase Galectin 3 TLRs VAP1 LPS CD3 NKT cell Adenosine A3R Based on Friedman et al, Nature Med, 2018 J Gregory 2016 Mount Sinai Health System Activated stellate cell FXR PPAR a, g, d CCR 2/5 ASK-1 Galectin 3 HSP 47 Aldosterone-R
Summary - How Will New Therapies Affect HCC Development? 1. Many potential mechanisms link inflammation to fibrosis and cancer in liver; some but not all are NASH-specific 2. Obesity directly increases the risk of all cancers. Persistent obesity will likely confer sustained risk. 3. The relative effects of NASH therapies on HCC will depend on the specific target (e.g., autophagy, immunity, microbiome), but no hierarchy of importance in HCC development has been established yet. 4. Because there are risk factors related to obesity and fat, reversal of fibrosis alone is unlikely to be sufficient to eliminate HCC risk.