Early detection of HCC using noninvasive activity-based nanosensors

Project Summary Abstract Hepatocellular carcinomaHCCis the most common primary liver cancer and arises from chronic liver diseasesCLDincluding hepatitis B virusHBVhepatitis C virusHCValcoholic liver diseaseALDand nonalcoholic steatohepatitisNASHTodaypatients with CLDs are at high risk for HCC and are monitored closely by imaging and serum biomarkersbut these platforms lack sensitivity for early stage HCCConsequentlyalthough HCC can be cured by surgical resectionless thanof the greater thannewly diagnosed HCC patients per year worldwide undergo surgical resection because of late diagnosisThis proposal aims to develop the Glympse liver testGLTa multiplexedinjectable diagnostic of activity based probeswhich detect the activity of proteases that drive the pathological hallmarks of early stage HCCThese HCC specific proteases are upregulated regardless of etiology and their activities drive fundamental tumor processes including angiogenesisinflammationand ECM degradationThe GLT platform is ultrasensitive to early stage HCC by relying on two mechanisms for signal amplificationdetection signals are generated by protease activity which amplifies signals by enzyme turnoverand are concentrated by renal filtration into urine for quantification by mass spectrometryWe will identify etiology independent HCC proteases and formulate GLT nanosensors on inert polymer scaffolds for human useWe will then validate the ability of GLT to detect early stage HCC in mouse models covering major etiologiesbenchmarking against imaging and serum biomarkersand then conduct preclinical toxicology studies in preparation for an IND submissionThe GLT offers clinician a rapid and sensitive diagnosis of early stage HCC compared to imaging and blood biomarkersThe ability of GLT to detect HCC at an early stage will significantly improve response ratesat Stagesavinglives frompatient deaths every yearThe benefit to the healthcare system will be greater than $million based on increasing the number of curative resection surgeries while significantly reducing the number of liver transplantsThe impact of the GLT for HCC will increase early stage diagnosis ratesreduce healthcare costs associated with treating late stage HCCand ultimately improve patient outcomes due to increased treatment options for physicians Project Narrative Hepatocellular carcinomaHCCarises from many different chronic liver diseases and if detected earlypatients can be cured by surgeryHowevercurrent diagnostic platforms including imaging and blood biomarkers are not sensitive for early stage diseaseThis project aims to develop an ultrasensitive urine diagnostic to detect early stage HCC to significantly increase patient response and cure rates to therapy