Blockade of growth hormone receptor signaling by using pegvisomant: A functional therapeutic strategy in hepatocellular carcinoma

Abstract

Hepatocellular carcinoma (HCC) is an aggressive neoplasm with poor clinical outcome because most patients present at an advanced stage, at which point curative surgical options, such as tumor excision or liver transplantation, are not feasible. Therefore, the majority of HCC patients require systemic therapy. Nonetheless, the currently approved systemic therapies have limited effects, particularly in patients with advanced and resistant disease. Hence, there is a critical need to identify new molecular targets and effective systemic therapies to improve HCC outcome. The liver is a major target of the growth hormone receptor (GHR) signaling, and accumulating evidence suggests that GHR signaling plays an important role in HCC pathogenesis. We tested the hypothesis that GHR could represent a potential therapeutic target in this aggressive neoplasm. We measured GH levels in 767 HCC patients and 200 healthy controls, and then carried out clinicopathological correlation analyses. Moreover, specific inhibition of GHR was performed in vitro using siRNA and pegvisomant (a small peptide that blocks GHR signaling and is currently approved by the FDA to treat acromegaly) and in vivo, also using pegvisomant. GH was significantly elevated in 49.5% of HCC patients, and these patients had a more aggressive disease and poorer clinical outcome (P<0.0001). Blockade of GHR signaling with siRNA or pegvisomant induced substantial inhibitory cellular effects in vitro. In addition, pegvisomant potentiated the effects of sorafenib (P<0.01) and overcame sorafenib resistance (P<0.0001) in vivo. Mechanistically, pegvisomant decreased the phosphorylation of GHR downstream survival proteins including JAK2, STAT3, STAT5, IRS-1, AKT, ERK, and IGF-IR. In two patients with advanced-stage HCC and high GH who developed sorafenib resistance, pegvisomant caused tumor stability. Our data show that GHR signaling represents a novel “druggable” target, and pegvisomant may function as an effective systemic therapy in HCC. Our findings could also lead to testing GHR inhibition in other aggressive cancers.

Plasma growth hormone is a potential biomarker of response to atezolizumab and bevacizumab in advanced hepatocellular carcinoma patients

“…Despite this recent breakthrough in the treatment of patients with advanced HCC, there remains an unmet need for reliable biomarkers of response to immunotherapy.GH level have been reported and validated as a prognostic marker in HCC patients [ 7 , 12 , 13 ]. Our group reported in previous studies the prognostic value of circulating GH level in all 767 patients with different disease stages and treatment modalities received and also compared them to healthy volunteers (200 cases) [ 2 , 13 ]. Our group also recently reported a significant correlation between GH level and overall survival [ 12 ].…”

“…More importantly, it provides the basis to investigate the potential integration of anti-GH strategies, such as pegvisomant; a short peptide that inhibits the GH/GHR signaling and is the only drug approved by FDA to treat acromegaly [ 14 ], into systemic therapy approaches in HCC. Our group recently reported that GHR signaling could be a potential successful target in HCC [ 13 ].…”

Growth Hormone Signaling in Liver Diseases: Therapeutic Potentials and Controversies

“…Pegvisomant (also referred to as Somavert) is an FDA-approved prescription medicine used for acromegaly patients and functions as a GHR antagonist to block GH/GHR signaling [56]. HCC cell lines, such as HepG2 cells, express higher levels of GHR compared to normal human liver cells, and pegvisomant treatment inhibited HCC tumor growth and increased sensitivity against sorafenib in HepG2 xenograft mouse models [55]. These findings indicate that abnormally elevated GH signaling may contribute to hepatic tumorigenesis and HCC…”

“…The majority of Ghr +/+ (93.5%) and Ghr +/-(87.1%) mice showed HCC development after DEN treatments, but 5.6% of Ghr -/mice developed HCC, indicating the vital roles of GH signaling in hepatic tumorigenesis and the therapeutic potentials of targeting GHR [54]. Kaseb et al analyzed plasma samples of 767 HCC patients and demonstrated that patients with high GH levels suffered more frequent cirrhosis, higher α-fetoprotein (AFP) levels, more advanced stages, and lower overall survival compared to patients with low GH plasma levels [55]. Interestingly, patients with high GH levels showed significantly lower circulating IGF1 levels than low GH patients [55].…”

“…Kaseb et al analyzed plasma samples of 767 HCC patients and demonstrated that patients with high GH levels suffered more frequent cirrhosis, higher α-fetoprotein (AFP) levels, more advanced stages, and lower overall survival compared to patients with low GH plasma levels [55]. Interestingly, patients with high GH levels showed significantly lower circulating IGF1 levels than low GH patients [55]. Pegvisomant (also referred to as Somavert) is an FDA-approved prescription medicine used for acromegaly patients and functions as a GHR antagonist to block GH/GHR signaling [56].…”