Patrick Starlinger, M.D., Ph.D.
Mayo Clinic,
Rochester, USA
Programm
“Decoding Human Liver Regeneration: From Molecular Mechanisms to Clinical Trials”
Background: Posthepatectomy liver failure (PHLF) remains a life-threatening complication of liver resection and a key determinant of surgical eligibility in patients with primary and metastatic liver tumors. Understanding the biological determinants of effective hepatic regeneration is essential for both mechanistic discovery and therapeutic innovation.
Translational Research & Biobank: To study human liver regeneration systematically, we established a prospective perioperative biobank, collecting longitudinal blood samples and paired liver tissue from patients undergoing partial hepatectomy. Leveraging this resource across a series of investigator-initiated projects, we identified several regeneration-associated biomarkers — including blood-derived microRNA signatures, von Willebrand factor antigen, activin A/follistatin-like 3 ratios, soluble TREM2, and perioperative GLP-1/GLP-2 dynamics — each capturing distinct dimensions of hepatic reserve and postoperative organ function.
Basic Science: Transcriptomic profiling of paired human liver specimens from patients with effective versus failed regeneration revealed divergent molecular programs governing regenerative success or collapse. Mechanistic projects anchored in the biobank identified YAP-1 tyrosine phosphorylation in biliary epithelial cells, DUSP4-mediated signaling, coagulation factor XIII activity, and neutrophil extracellular trap formation as context-dependent regulators of hepatocyte proliferation and perioperative liver dysfunction — findings further refined through experimental murine partial hepatectomy models.
Clinical Biomarker Development: Biobank-derived insights were prospectively validated and consolidated into the APRI+ALBI multivariable risk model, externally validated in over 14,000 patients across 10 international centers and implemented as the TELLaprialbi smartphone application — providing a globally accessible, biopsy-free tool for preoperative PHLF risk stratification.
Clinical Trials: Building on this mechanistic and biomarker foundation, our group is now engaged in two prospective interventional trials. The first (NCT06638502) evaluates HRX215 — an orally available, first-in-class inhibitor of MKK4, a key negative regulator of hepatocyte proliferation — in patients undergoing minor and major liver resection for colorectal metastases at Mayo Clinic, with the minor resection cohort already completed with a clean safety profile. The second, the international multicenter DRAGON-PLC trial (NCT06914648), addresses the challenge of insufficient future liver remnant (FLR) volume in primarily unresectable primary liver cancers by randomizing patients to combined portal and hepatic vein embolization versus standard portal vein embolization alone, with resectability and five-year overall survival as co-primary endpoints.
Host: Alice ASSINGER