Abstract
ABSTRACTSorafenib 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 following in vivo sorafenib 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 vitro sorafenib 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.
Highlights
Hepatocellular carcinoma (HCC) is the fifth-most common cancer and the third leading cause of cancer-related mortality globally.[1]
Abou-Alfa et al studied the gene expression profiles of HCC patients using RNA extracted from patient PBMCs; these studies could not elucidate any functional roles for the panel of genes that distinguished nonprogressors from progressors.[3]
PBMCs isolated from blood samples collected from patients with advanced HCC who were to commence sorafenib therapy were the source of endothelial progenitor cells (EPCs)
Summary
Hepatocellular carcinoma (HCC) is the fifth-most common cancer and the third leading cause of cancer-related mortality globally.[1]. HCC patients are frequently diagnosed at a late stage of disease progression or with deteriorated liver function, thereby, precluding surgical intervention. Liver transplantation is indicated only for patients at the initial stage of disease development and its application is critically dependent on availability of donor liver. Treatment options for patients with advanced stage disease are limited to chemoembolization or systemic therapy with sorafenib, an oral anti-angiogenic agent which is the mainstay of treatment for these patients. Sorafenib was the first drug to show improvement in both progression free and overall survival among patients with advanced disease.[2] these treatment approaches have led to improved clinical response rates, treatment associated toxicities are frequent, requiring dose interruptions and reductions for the majority of patients. Survival remains less than 1 y for patients with advanced stage disease who are eligible for such molecularly targeted therapies
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