title: Endothelial progenitor cell number and ERK phosphorylation serve as predictive and prognostic biomarkers in advanced hepatocellular carcinoma patients treated with sorafenib.
abstract: Sorafenib is an oral anti-angiogenic multi-kinase inhibitor used for systemic therapy in patients with advanced hepatocellular carcinoma (HCC) who are not suitable candidates for surgery or liver transplantation. An earlier study conducted with HCC tumor tissue suggested that ERK phosphorylation (pERK), a downstream target of sorafenib, may serve as a potential biomarker for therapeutic efficacy of sorafenib. However, no study thus far has utilized a minimal invasive procedure to predict HCC patient responsiveness to sorafenib. We evaluated the biomarker utility of circulating endothelial progenitor cells (EPCs) frequency and intracellular pERK levels in EPCs in peripheral blood obtained pre- and post-sorafenib therapy or after transarterial chemoembolistaion (TACE). A statistically significant reduction in the level of ERK phosphorylation and in the absolute number of EPCs was detected followingin vivosorafenib treatment (p< 0 .01 for both). In contrast, the decrease in the level of ERK phosphorylation and EPC number was either marginally significant or insignificant in patients treated with TACE (p= 0.05 and 0.06, respectively).In vitrosorafenib treatment of pre- and post-samples from the same patient cohort inhibited ERK phosphorylation levels in EPCs and decreased the number of EPCs at all doses tested (p= 0.01). Our findings support that the evaluation of both the circulating EPC frequency and the level of ERK phosphorylation in EPCs may serve as potential non-invasive biomarkers of sorafenib efficacy, both as predictor of treatment outcome and efficacy during drug treatment.
authors.affiliation: Department of Immunology, Roswell Park Cancer Institute , Buffalo, NY, USA.
authors.forename: Suresh Gopi
authors.initials: SG
authors.lastname: Kalathil
authors.affiliation: Department of Immunology, Roswell Park Cancer Institute , Buffalo, NY, USA.
authors.forename: Amit Anand
authors.initials: AA
authors.lastname: Lugade
authors.affiliation: Department of Medicine, Roswell Park Cancer Institute , Buffalo, NY, USA.
authors.forename: Renuka
authors.initials: R
authors.lastname: Iyer
authors.affiliation: Department of Biostatistics & Bioinformatics, Roswell Park Cancer Institute , Buffalo, NY, USA.
authors.forename: Austin
authors.initials: A
authors.lastname: Miller
authors.affiliation: Department of Immunology, Roswell Park Cancer Institute , Buffalo, NY, USA.
authors.forename: Yasmin
authors.initials: Y
authors.lastname: Thanavala
keywords: Anti-VEGF therapy; ERK phosphorylation; biomarker; endothelial progenitor cells; hepatocellular carcinoma; sorafenib