Biomarkers and overall survival in patients with advanced hepatocellular carcinoma treated with TGF-βRI inhibitor galunisertib

PLoS One. 2020 Mar 25;15(3):e0222259. doi: 10.1371/journal.pone.0222259. eCollection 2020.


Background: Transforming growth factor beta (TGF-β) signalling is involved in the development of hepatocellular carcinoma (HCC). We followed changes in biomarkers during treatment of patients with HCC with the TGF-βRI/ALK5 inhibitor galunisertib.

Methods: This phase 2 study (NCT01246986) enrolled second-line patients with advanced HCC into one of two cohorts of baseline serum alpha-fetoprotein (AFP): Part A (AFP ≥1.5x ULN) or Part B (AFP <1.5x ULN). Baseline and postbaseline levels of AFP, TGF-β1, E-cadherin, selected miRNAs, and other plasma proteins were monitored.

Results: The study enrolled 149 patients (Part A, 109; Part B, 40). Median OS was 7.3 months in Part A and 16.8 months in Part B. Baseline AFP, TGF-β1, E-cadherin, and an additional 16 plasma proteins (such as M-CSF, IL-6, ErbB3, ANG-2, neuropilin-1, MIP-3 alpha, KIM-1, uPA, IL-8, TIMP-1, ICAM-1, Apo A-1, CA-125, osteopontin, tetranectin, and IGFBP-1) were found to correlate with OS. In addition, a range of miRs were found to be associated with OS. In AFP responders (21% of patients in Part A with decrease of >20% from baseline) versus non-responders, median OS was 21.5 months versus 6.8 months (p = 0.0015). In TGF-β1 responders (51% of all patients) versus non-responders, median OS was 11.2 months versus 5.3 months (p = 0.0036).

Conclusions: Consistent with previous findings, both baseline levels and changes from baseline of circulating AFP and TGF-β1 function as prognostic indicators of survival. Future trials are needed to confirm and extend these results.

Publication types

  • Clinical Trial, Phase II
  • Multicenter Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Antigens, CD / blood
  • Biomarkers, Tumor / blood
  • Cadherins / blood
  • Carcinoma, Hepatocellular / blood
  • Carcinoma, Hepatocellular / drug therapy*
  • Carcinoma, Hepatocellular / mortality*
  • Cohort Studies
  • Female
  • Humans
  • Liver Neoplasms / blood
  • Liver Neoplasms / drug therapy*
  • Liver Neoplasms / mortality*
  • Male
  • MicroRNAs / blood
  • Middle Aged
  • Prognosis
  • Pyrazoles / pharmacology*
  • Pyrazoles / therapeutic use*
  • Quinolines / pharmacology*
  • Quinolines / therapeutic use*
  • Receptor, Transforming Growth Factor-beta Type I / antagonists & inhibitors*
  • Survival Rate
  • Transforming Growth Factor beta1 / analysis
  • Treatment Outcome
  • alpha-Fetoproteins / analysis


  • AFP protein, human
  • Antigens, CD
  • Biomarkers, Tumor
  • CDH1 protein, human
  • Cadherins
  • MicroRNAs
  • Pyrazoles
  • Quinolines
  • TGFB1 protein, human
  • Transforming Growth Factor beta1
  • alpha-Fetoproteins
  • LY-2157299
  • Receptor, Transforming Growth Factor-beta Type I
  • TGFBR1 protein, human

Associated data


Grant support

This study was funded by Eli Lilly and Company, Indianapolis, IN, USA ( Employees of Eli Lilly and Company designed the study, analyzed the data, were authors on the manuscript, and approved the manuscript for publication.