Project Grant R21CA280444

NOVEL CIRCULATING BIOMARKER DIGITAL SCORES FOR ASSESSING TREATMENT RESPONSE IN LIVER CANCER - PROJECT SUMMARY/ABSTRACT HEPATOCELLULAR CARCINOMA (HCC) IS ONE OF THE LEADING CAUSES OF CANCER-RELATED DEATHS WORLDWIDE. LOCAL ABLATION AND TRANSARTERIAL CHEMOEMBOLIZATION (TACE) ARE THE MOST COMMONLY USED TREATMENT MODALITY FOR HCC. FOLLOWING TREATMENT, PATIENTS UNDERGO RADIOLOGIC IMAGING FOR EVALUATION OF TREATMENT RESPONSE. ASSESSING TREATMENT RESPONSE TO LOCAL ABLATION OR TACE IS OFTEN CHALLENGING DUE TO TREATMENT-RELATED NONSPECIFIC CHANGES AND DEFINITIVE ASSESSMENT TYPICALLY REQUIRES REPEATED CROSS-SECTIONAL IMAGING. SIMILARLY, THERE IS POOR RADIOLOGIC-HISTOLOGICAL CORRELATION OF POST-TREATMENT TUMOR VIABILITY, WITH DISCORDANT RESULTS SEEN IN 38% OF HCC PATIENTS AFTER LOCAL ABLATION OR TACE. WHILE SERUM ALPHA-FETOPROTEIN (AFP) CAN AID IN ASSESSING TREATMENT RESPONSE, LESS THAN HALF OF ALL PATIENTS WITH HCC HAVE AN ELEVATED AFP BEFORE TREATMENT. THIS LIMITS ITS UTILITY FOR BROADER IMPLEMENTATION. THE MAIN OBJECTIVE OF THIS R21 PROPOSAL IS TO INVESTIGATE THE PERFORMANCE OF NOVEL CIRCULATING BIOMARKER DIGITAL SCORES FOR EVALUATION OF HCC TREATMENT RESPONSE. RECENTLY, DRS. ZHU (PI) AND TSENG (CO-INVESTIGATOR) HAS DEVELOPED A STREAMLINED HCC EXTRACELLULAR VESICLES (EV) DIGITAL SCORING ASSAY THAT COUPLES TWO ROBUST TECHNOLOGIES, I.E., EV CLICK CHIP FOR PURIFICATION OF HCC EVS AND REVERSE-TRANSCRIPTION DROPLET DIGITAL PCR (RT-DDPCR) FOR QUANTIFICATION OF HCC-SPECIFIC MRNA MARKERS WITH OUTSTANDING PERFORMANCE FOR EARLY-STAGE HCC DETECTION. BESIDES, DR. YANG (CONTACT-PI) DEMONSTRATED THAT THE GALAD SCORE, DERIVED FROM THREE HCC PROTEIN TUMOR MARKERS (AFP-L3, AFP, AND DES- CARBOXYPROTHROMBIN) IS HIGHLY ACCURATE FOR THE DETECTION OF EARLY-STAGE HCC. BOTH SCORES REFLECT TUMOR BURDEN AND OUR PILOT DATA SHOWED THEIR PROMISING PERFORMANCE IN ASSESSING TREATMENT RESPONSE. THUS, THE CENTRAL HYPOTHESIS OF THIS R21 PROPOSAL IS THAT PRE- AND POST-TREATMENT HCC EV DIGITAL SCORE, GALAD SCORE, AND INTEGRATION OF TWO INDEPENDENT SCORES (I.E., HCC EV-GALAD DIGITAL SCORE) CAN EVALUATE HCC TREATMENT RESPONSE. DR. YANG AND DR. ZHU WILL CONDUCT BIOMARKER STUDIES TO TEST THE HYPOTHESIS. THIS PROJECT IS INNOVATIVE AS IT LEVERAGES TWO ORTHOGONAL BIOMARKER SCORES; A NOVEL HCC EV DIGITAL SCORE AND PROMISING SERUM PROTEIN- BASED SCORE. THE LONG-TERM GOAL OF THIS R21 PROPOSAL IS TO DETERMINE THE PERFORMANCE OF HCC EV, GALAD, AND HCC EV-GALAD DIGITAL SCORES FOR EVALUATING HCC TREATMENT RESPONSE AND VALIDATE THEIR PERFORMANCE IN AN INDEPENDENT COHORT.