Tuesday, January 31, 2023
1/31/2023
PROJECT SUMMARY/ABSTRACT Hepatocellular carcinoma (HCC) is a leading cause of cancer mortality worldwide and its incidence is rising in both men and women in the United States. Anti-PD1 and anti-PD-L1 immune checkpoint inhibitor (ICI) antibodies are now FDA approved for advanced HCC, however, as few as 20% of patients receiving these agents will show an objective response to therapy. Because immune-related adverse events are non-trivial, predictive biomarkers that can explain the variability in immunotherapy response are needed to optimize patient selection. Several lines of research have recently converged to associate oncogenic activation of the Wnt/beta- catenin signaling pathway with tumor immune-evasion and poor clinical response to ICI therapy in HCC. In previous research, we found that HCC exhibiting high uptake of the positron emission tomography / computed tomography (PET/CT) imaging agent 18F- fluorocholine (FCH) often belonged to molecular tumor sub-types associated with beta-catenin activation and immune avoidance. Liquid biopsy based on targeted sequencing of cell-free DNA (cfDNA) has also made it possible to identify patients who have tumors that harbor mutations associated with increased Wnt/beta-catenin signaling. This project comprises a phase 2 biomarker clinical trial to prospectively evaluate these specific embodiments of PET/CT and liquid biopsy as tools for detecting HCC recalcitrant to ICI therapy on the basis of beta-catenin activation. In addition to characterizing and comparing the predictive capabilities of FCH PET/CT and cfDNA mutation profiling based on phase 2 clinical endpoints, this project will utilize decision tree based machine learning to estimate the predictive performance of an integrative imaging-genomic biomarker while also further examining how tumor mutations are related to PET metabolic phenotype and immunotherapy response. Furthermore, because tumor 18F-fluorodeoxyglucose (FDG) uptake is incongruent with FCH uptake in HCC, a third aim will utilize the trial as a molecular screening process to create an enriched sub-cohort of patients with FDG-avid tumors. These patients will undergo serial FDG PET/CT to evaluate FDG as a source of predictive biomarkers of ICI response for an orthogonal molecular sub-type of HCC. If these diagnostic tests are found reliable at predicting tumor resistance/response, they could significantly enhance the clinical precision and overall benefit of immunotherapy for HCC and possibly other cancers.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).
