MKK4 Regulation of Liver Regeneration after Resection of Colorectal Metastasis or Hilar Cholangiocarcinoma

Mayo Clinic Rochester, Rochester MN

Investigators

Abstract

PROJECT SUMMARY The extent of resection and size of the functional liver remnant after major hepatectomy for liver cancer are major factors affecting patient outcome and risk of post-hepatectomy liver failure. Therefore, therapies that stimulate liver regeneration without increasing the risk of tumor growth are vital to improving outcomes. Preliminary work by our German collaborators identified the dual-specific MAP2 kinase MKK4 as a master regulator of hepatocytic regeneration. In collaboration, we have identified a novel compound, HRX215, a highly selective small molecule MKK4 inhibitor with favorable pharmacokinetics that induced striking liver regeneration after partial hepatectomy in murine and porcine models of acute liver damage. Based on these favorable preclinical data, we hypothesize that HRX215 can promote liver regeneration in human patients. In the proposed phase 2b clinical trial, we will examine the effects of HRX215 in human patients receiving major hepatectomy at a single center, Mayo Clinic, Rochester, MN. In Aim 1, eighty patients undergoing portal vein embolization before major hepatectomy for colorectal cancer liver metastases will be randomized equally into treatment or control groups. Treatment patients will be administered 250 mg (PO) HRX215 twice daily for 28 days, initiated 12 hours before portal vein embolization. Control patients will receive a placebo. All patients will undergo volumetric computed tomography (CT) scanning before and on day 7 and day 28 after portal vein embolization. We hypothesize that the functional liver remnant in treatment patients receiving HRX215 will experience greater volumetric gain (indicating faster regeneration), and allow resection earlier and in a higher percentage of patients compared to the control group. In Aim 2, 40 patients undergoing major hepatectomy for hilar cholangiocarcinoma will be randomized equally into control and treatment groups, with control patients receiving a placebo and treatment patients receiving 250 mg (PO) HRX215 twice daily for 28 days following surgery. Both groups of cholangiocarcinoma patients will receive standard care, with volumetric CT scanning performed before and on day 7 and day 28 after resection. We hypothesize that patients administered HRX215 will have faster volumetric gain and reduced incidence of post-hepatectomy liver failure compared to control patients. Finally, we will use blood and tissue samples to measure intrahepatic neutrophil accumulation, quantify circulating myeloperoxidase and inflammatory factors, and perform spatial transcriptomics on the regenerating liver. These data will be used to determine the predictive value of novel blood and intrahepatic tissue markers in determining outcomes after surgery and estimating the risk of PHLF. We hypothesize that HRX215 will reduce post-resection inflammation and this response will correlate with better clinical outcomes. We believe these human trials could lead to new treatments for patients receiving major hepatectomy and identify a novel drug target for enhancement of liver regeneration.