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Principal Investigator: Han-Yu Chuang
Organization: EXIMIUS DIAGNOSTICS CORP
Fiscal Year: 2024
Award: $661,609
Funding agency: National Cancer Institute
PROJECT SUMMARY
Hepatocellular carcinoma (HCC) comprises 80-85% of primary liver cancers and frequently develops in patients
with liver cirrhosis or chronic hepatitis B virus infection. HCC's poor prognosis is primarily due to advanced-stage
diagnosis. Current clinical practice guidelines recommend biannual liver ultrasounds, with or without serum
alpha-fetoprotein (AFP) testing, for at-risk patients to detect HCC at a curable stage. However, their accuracy is
limited, with sensitivity between 60-70% and specificity of 90%. Consequently, novel biomarkers for early
detection of HCC are urgently needed. Extracellular vesicles (EVs) are a heterogeneous group of lipid
nanoparticles that are released by all types of cells, and even more so by tumor cells. Tumor-derived EVs are
present in circulation at relatively early stages of disease and are readily accessible across all disease stages.
Since the surface proteins of tumor EVs mirror those of the parental tumor cells and those cells within tumor
microenvironment, exploiting the diagnostic potential of HCC EVs’ surface protein signatures as a novel
biomarker for early detection of HCC holds great promise to significantly augment the ability of current diagnostic
modalities.
Over the last five years, our joint team comprised of Eximius Dx, UCLA, and Cedars Sinai Medical Center
(CSMC) has demonstrated of HCC EV Surface Protein (SP) Test, capable of dissecting and quantifying
subpopulations of HCC EVs in plasma samples. In our 2022 Hepatology paper, we summarized a phase-2
biomarker study which successfully validated the feasibility of HCC EV SP Test for early HCC detection. The
long-term goal of this Direct-to-Phase-II proposal is to advance the development, optimization, and automation
of the HCC EV SP Test, with the ultimate goal of establishing a more sensitive in vitro diagnostic (IVD) test based
on HCC EVs. The innovation of the proposed HCC EV SP Test lies in the integration of two platform technologies:
(i) EV Click MagBeads for click chemistry-mediated capture of subpopulations of HCC EVs, and (ii) real-time
immuno-PCR for quantifying the captured HCC EVs. In parallel, an algorithm will be established to process the
resulting HCC EV signatures into HCC EV SP score for distinguishing early-stage HCC from at-risk cirrhosis.
This new IVD test will use less then 1-mL plasma and have a sample-to-answer workflow of no more than 3
hours. By adopting an in-house developed robotic system, the automated workflow allows for a throughput >
480 samples per round. Once optimized and automated the HCC EV SP Test will be validated by clinically
annotated plasma samples to assess its diagnostic performance for distinguishing early-stage HCC from at-risk
liver cirrhotic patients, covering etiologies including alcohol-associated liver disease (ALD), non-alcoholic fatty
liver disease (NAFLD), and viral hepatitis (B/C). The successful development of the proposed HCC EV SP Test
is rapidly translatable, enabling a sensitive HCC EV-based IVD test for detecting early-stage HCC.
Terms: <ANX5><ANX5 Gene><ANXA5><ANXA5 gene><Ablation><Abscission><Adopted><Advanced Development><Affect><Alcoholic Liver Diseases><Algorithms><Alpha-1-Fetoprotein><Alpha-Fetoglobulin><Anchorin CII><Anchorin CII Gene><Annexin A5 Gene><Annexin A5 Protein><Annexin V><Antibodies><Antigen Defined by Monoclonal Antibody AUAI><Automation><Bar Codes><Bio-Informatics><Bioinformatics><Biological Markers><Biometrics><Biometry><Biostatistics><Blood Circulation><Blood Plasma><Blood Serum><Bloodstream><CBP-I><CD81><CD81 gene><Calphobindin I><Cancer Cause><Cancer Etiology><Case-Base Studies><Case-Comparison Studies><Case-Compeer Studies><Case-Referent Studies><Case-Referrent Studies><Case/Control Studies><Causality><Cell Body><Cells><Cessation of life><Chemistry><Chronic Hepatitis B><Circulation><Cirrhosis><Clinical><Clinical Practice Guideline><DNA><Death><Deoxyribonucleic Acid><Detection><Development><Diagnosis><Diagnostic><Diagnostic tests><Disease><Disorder><ENX2><ENX2 Gene><Early Diagnosis><Echography><Echotomography><Endonexin II><Endonexin II Gene><EpCAM><Epithelial Cellular Adhesion Molecule><Etiology><Excision><Exhibits><Extirpation><Fetuins><GA733-2><GPC3><GPC3 gene><Gastrointestinal Tumor-Associated Antigen 2, 35-KD Glycoprotein><Glypican 3><Goals><Guidelines><HCC cell><HCC cell line><HCV infection><Hepatic Cirrhosis><Hepatic Disorder><Hepatic Transplantation><Hepatitis B><Hepatitis C><Hepatitis C virus infection><Hepatitis, Viral, Non-A, Non-B, Parenterally-Transmitted><Hepatitus C><Hepatocarcinoma><Hepatocellular Carcinoma><Hepatocellular cancer><Hepatology><Hepatoma><Hour><Individual><Joints><Lipocortin V Gene><Lipocortin-V><Liver><Liver Cells Carcinoma><Liver Cirrhosis><Liver Grafting><Liver Transplant><Liver diseases><M4S1><MIC18><Mediating><Medical Ultrasound><Medical center><Membrane Component, Chromosome 4, Surface Marker 1><Membrane Protein Gene><Membrane Proteins><Membrane-Associated Proteins><Methods><Modality><Motivation><NAFLD><Oncology><Oncology Cancer><Operative Procedures><Operative Surgical Procedures><PAP-I><PP4 Gene><Paper><Pathology><Patients><Performance><Phase><Phosphatides><Phospholipids><Placental Anticoagulant Protein I><Placental Protein 4><Plasma><Plasma Serum><Primary Malignant Neoplasm of Liver><Primary carcinoma of the liver cells><Primary liver cancer><Process><Prognosis><Protein Analysis><Quantitative Evaluations><Rat Homolog of OCI-5><Recommendation><Removal><Research><Research Specimen><Reticuloendothelial System, Serum, Plasma><Risk><Robotics><SBIR><Sampling><Serum><Site><Small Business Innovation Research><Small Business Innovation Research Grant><Specificity><Specimen><Surface><Surface Proteins><Surgical><Surgical Interventions><Surgical Procedure><Surgical Removal><System><Systems Development><TACSTD1><TACSTD1 gene><TAPA-1><TAPA1><TSPAN28><Testing><Thromboplastin Inhibitor><Time><Training><Tumor Cell><Tumor-Associated Calcium Signal Transducer 1><Tumor-Derived><Ultrasonic Imaging><Ultrasonogram><Ultrasonography><Ultrasound Diagnosis><Ultrasound Medical Imaging><Ultrasound Test><VAC-Alpha><Validation><Vascular Anticoagulant-Alpha><Viral Hepatitis B><Viral hepatitis><alcohol induced hepatic injury><alcohol induced liver disorder><alcohol induced liver injury><alcohol related liver disease><alcohol-associated liver disease><alcohol-induced hepatic dysfunction><alcohol-induced liver disease><alcohol-induced liver dysfunction><alcohol-mediated liver dysfunction><alcohol-mediated liver injury><alcohol-related liver disease><alcoholic liver injury><annexin A5><arm><assay development><barcode><bio-markers><biologic marker><biomarker><biomarker development><cancer microenvironment><case-controlled studies><causation><cell type><chronic HBV infection><chronic hepatitis B virus infection><circulating biomarkers><circulating markers><cirrhotic><clinical practice and guidelines><cohort><computer based prediction><detection sensitivity><developmental><diagnostic ability><diagnostic capability><diagnostic power><diagnostic ultrasound><diagnostic utility><diagnostic value><disease causation><early biomarkers><early detection><early detection biomarkers><early detection markers><ethanol induced hepatic injury><ethanol induced liver disorder><ethanol induced liver injury><ethanol liver disease><ethanol-induced hepatic dysfunction><ethanol-induced liver disease><ethanol-induced liver dysfunction><ethanol-mediated liver dysfunction><ethanol-mediated liver injury><extracellular vesicles><hep C><hepatic body system><hepatic disease><hepatic organ system><hepatitis non A non B><hepatitis virus infection><hepatocellular carcinoma cell line><hepatopathy><in-vitro diagnostics><infection by hepatitis c virus><innovate><innovation><innovative><lipid based nanoparticle><lipid nanoparticle><liquid biopsy><liver carcinoma><liver disorder><liver transplantation><molecular pathology><nano particle><nano-sized particle><nanoparticle><nanosized particle><neoplastic cell><new marker><non A, non B hepatitis><non-A, non-B hepatitis><non-alcohol fatty liver disease><non-alcoholic fatty liver disease><non-alcoholic liver disease><nonalcoholic fatty liver disease><novel biomarker><novel marker><predictive modeling><product development><resection><robotic system><serum hepatitis><sonogram><sonography><sound measurement><surgery><technology platform><technology system><tumor><tumor microenvironment><ultrasound><ultrasound imaging><ultrasound scanning><validations><α-Fetoproteins>