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Principal Investigator: Paul J Brindley
Organization: GEORGE WASHINGTON UNIVERSITY
Fiscal Year: 2024
Award: $382,600
Funding agency: National Cancer Institute
Project Summary
Liver fluke infection with Opisthorchis viverrini remains problematic in East Asia and is endemic in Thailand and
Laos, where ~10 million people are infected. The public health implications of this situation are substantial since
there is no stronger link between a human malignancy and a eukaryotic pathogen than that between
cholangiocarcinoma (CCA, bile duct cancer) and infection with O. viverrini. Northeast Thailand reports the
highest incidence of CCA worldwide, with the 2014 CCA age standardized incidence rate (ASR) of 85 per
100,000, which equates to 26,000 CCA-related deaths annually. The contrast with countries without liver flukes
is stark given that incidence of CCA is less than 3 per 100,000 elsewhere (USA, 1.67 ASR, 2014).
To survive in the biliary tract, the liver fluke actively releases excretory/secretory (ES) proteins and
extracellular vesicles (EVs) that facilitate fluke feeding and manipulation of the host immune response, and
ultimately modify cellular homeostasis that contributes to malignant transformation. Our hypothesis is that
targeting proteins that are essential for several discrete facets of parasitism and/or are known carcinogens via a
multi-valent vaccine will deliver a novel anti-infection/ anti-cancer therapy. We will address this hypothesis
through the following aims: Aim 1. Explore the importance of key fluke ES proteins in host-parasite
communication and leverage the findings to prioritize their selection as vaccine antigens. Aim 2. Determine
whether mRNA and/or protein subunit vaccines induce antibodies that reduce both fluke burdens and CCA
incidence in the hamster infection-cancer model. This proposal targets liver fluke ES proteins which drive the
phenotypic hallmarks of cancer in the biliary epithelium: 1) the granulin-like growth factor, Ov-GRN-1, known to
induce rampant cholangiocyte proliferation; 2) the tetraspanin, Ov-TSP-2, a key element of EVs and host-cell
communication; 3) the Ov-catF cysteine protease, a key component of the protein digestion cascade; and 4) the
Ov-M60mucinase which degrades host defensive mucus in the bile ducts.
The conceptual innovation we utilize is a rodent model of human carcinogenesis where liver fluke
infection is a known risk factor. Technical innovations include gene knockout in the liver fluke, targeting key
pathogenic and nutritional processes, and combining the findings to develop vaccination against fluke infection
and the infection-induced cancer. These studies will determine whether fluke proteins that communicate at the
host-parasite interface represent the Achilles’ heel of this carcinogenic parasite. Targeting fluke-host
communication in combination with nutrient acquisition pathways may ultimately combat liver fluke-induced bile
duct cancer in the form of an anti-fluke, and indeed anti-cancer vaccine, a public health development with the
potential to benefit millions of (often impoverished) residents of endemic regions in East Asia.
Terms: <Address><Adjuvant><Age><Antigen Targeting><Antigens><Antineoplastic Vaccine><Area><Asian><Autoregulation><Award><Bile Duct Cancer><Bile Duct Carcinoma><Bile Tract><Biliary><Biliary System><Biliary Tree><Biochemical><Biological><Biological Symbiosis><Blood Serum><CRISPR approach><CRISPR based approach><CRISPR method><CRISPR methodology><CRISPR technique><CRISPR technology><CRISPR tools><CRISPR-CAS-9><CRISPR-based method><CRISPR-based technique><CRISPR-based technology><CRISPR-based tool><CRISPR/CAS approach><CRISPR/Cas method><CRISPR/Cas technology><CRISPR/Cas9><CRISPR/Cas9 technology><Cancer Causing Agents><Cancer Induction><Cancer Model><Cancer Treatment><Cancer Vaccines><CancerModel><Cancers><Carcinogens><Cas nuclease technology><Caspase><Caspase Gene><Cell Communication><Cell Growth in Number><Cell Interaction><Cell Multiplication><Cell Proliferation><Cell-Death Protease><Cell-to-Cell Interaction><Cellular Proliferation><Cervical cancer vaccine><Cessation of life><Cholangiocarcinoma><Cholangiocellular Carcinoma><Clinic><Clustered Regularly Interspaced Short Palindromic Repeats approach><Clustered Regularly Interspaced Short Palindromic Repeats method><Clustered Regularly Interspaced Short Palindromic Repeats methodology><Clustered Regularly Interspaced Short Palindromic Repeats technique><Clustered Regularly Interspaced Short Palindromic Repeats technology><Co-culture><Cocultivation><Coculture><Coculture Techniques><Combination Vaccines><Combined Vaccines><Communication><Complement><Complement Proteins><Country><Cricetinae><Cysteine Endopeptidases><Cysteine Protease><Cysteine Proteinases><Data><Death><Development><Digestion><ELISA><East Asia><Eastern Asia><Elements><Encapsulated><Enzyme-Linked Immunosorbent Assay><Epithelium><Equation><Far East><Fasciola hepatica><Fibrosis><Flukes><Funding><Goals><Growth Agents><Growth Factor><Growth Substances><HPV><Hamsters><Hamsters Mammals><Helminths><Hepatic Cancer><Hepatocarcinogenesis><Homeostasis><Human><Human Papilloma Virus><Human Papillomavirus><ICE-like protease><IgE><Immune response><Immunoglobulin E><Immunological response><Impoverished><In Vitro><Incidence><Infection><Infectious Human Wart Virus><Interruption><Lao People's Democratic Republic><Laos><Link><Liver Carcinogenesis><Liver Fluke><Low-resource area><Low-resource community><Low-resource environment><Low-resource region><Low-resource setting><Malignant><Malignant - descriptor><Malignant Neoplasm Therapy><Malignant Neoplasm Treatment><Malignant Neoplasms><Malignant Tumor><Malignant neoplasm of liver><Messenger RNA><Modeling><Modern Man><Molecular><Mucous body substance><Mucus><NIAID><National Institute of Allergy and Infectious Disease><Neoplasm Vaccines><Nutrient><Nutritional><Oncogens><Opisthorchis viverrini><Organoids><Parasites><Parasitic Worms><Pathogenesis><Pathogenicity><Pathogenicity Factors><Pathology><Pathway interactions><Persons><Phenotype><Physiological Homeostasis><Population><Poverty><Preparation><Process><Proepithelin Conversion to Epithelin and Wound Repair Control><Prognosis><Proliferating><Property><Protein Subunits><Proteins><Proteins Growth Factors><Public Health><RNA vaccine><RNA-based vaccine><Recombinant Proteins><Reporting><Resource-constrained area><Resource-constrained community><Resource-constrained environment><Resource-constrained region><Resource-constrained setting><Resource-limited area><Resource-limited community><Resource-limited environment><Resource-limited region><Resource-limited setting><Resource-poor area><Resource-poor community><Resource-poor environment><Resource-poor region><Resource-poor setting><Risk><Risk Factors><Rodent Model><Role><Safety><Sampling><Serum><Standardization><Subunit Vaccines><TSP-2><TSP2><Testing><Thailand><Therapeutic><Thrombospondin II><Trematoda><Tumor Vaccines><Vaccination><Vaccine Antigen><Vaccines><Virulence Factors><Wound Repair><Wound Repair Pathway><ages><anti-cancer><anti-cancer therapy><anti-tumor vaccine><bile duct><bile ductule><biliary cancer><biliary tract><biobank><biologic><biorepository><cancer therapy><cancer-directed therapy><carcinogenesis><carcinogenesis in the liver><carcinogenicity><cholangiocyte><cholangiosarcoma><chronic skin wound><chronic wound><cohort><combat><complementation><cystein protease><cystein proteinase><cysteine endopeptidase><developmental><egg><enzyme linked immunoassay><extracellular><extracellular vesicles><feeding><fitness><food-born><food-borne><foodborn><foodborne><functional genomics><granulin><hepatic carcinogenesis><hepatocellular carcinogenesis><host response><human model><immune system response><immunization strategy><immunogen><immunogenic><immunoresponse><in vivo><innovate><innovation><innovative><knockout gene><liver cancer><liver cancer pathogenesis><liver malignancy><liver tumorigenesis><mRNA><mRNA vaccine><mRNA-based vaccine><malignancy><malignant liver tumor><model of human><mucous><neoplasm/cancer><novel><nutrition><nutritious><oncogenic agent><parasitism><pathogen><pathway><preparations><repair><repaired><response><secretory protein><sheep liver fluke><social role><thrombospondin 2><translational opportunities><translational potential><vaccination strategy><vaccine antibodies><vaccine candidate><vaccine efficacy><vaccine for cancer><vaccine induced antibodies><vaccine-induced antibodies><wart virus><wound healing><wound recovery><wound resolution>