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

Kaseb AO, Haque A, Vishwamitra D, Hassan MM, Xiao L, George B, Sahu V, Mohamed YI, Carmagnani Pestana R, Lombardo JL, Avritscher R, Yao JC and 4 more

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Wolff RA, Rashid A, Morris JS, Amin HM

Frontiers in oncology6 Oct 2022Cited by 19 (Europe PMC)

PMID36276070PMCIDPMC9582251DOI10.3389/fonc.2022.986305PepBankPUB-36276070

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Summary

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 (Pin 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.

CC BYText from Europe PMC. Highlighted sentences are the source of results.

Results from this study5

5 results from studies that gave the peptide. 1 result from people.

01HumanCase report or seriesEfficacy outcome
In two patients with advanced hepatocellular carcinoma, high GH, and sorafenib resistance, pegvisomant was associated with tumor stability.
In plain wordsIn two patients with advanced liver cancer and sorafenib resistance, pegvisomant was linked to stable tumors.
Peptide
Pegvisomant
Outcome
Direction not reportedTumor stability
Study
n = 2
Outcome group
Tumor growth · Cancer
Studied dose
Dose not stated
Source sentences
Summary
In two patients with advanced-stage HCC and high GH who developed sorafenib resistance, pegvisomant caused tumor stability.
Show in the study text Report a problemFND-3627607004
02AnimalAnimal study (in vivo)Efficacy outcome
In an in vivo hepatocellular carcinoma model, added pegvisomant potentiated sorafenib effects (P<0.01).
In plain wordsIn an animal liver cancer model, added pegvisomant increased sorafenib effects compared with sorafenib without pegvisomant.
Peptide
Pegvisomant
Outcome
IncreaseSorafenib effect potentiation
Study
n: not reported in source
Hepatocellular carcinoma in vivo model
Comparator
Sorafenib without pegvisomant
Outcome group
Tumor growth · Cancer
Studied dose
Dose not stated
Source sentences
Summary
In addition, pegvisomant potentiated the effects of sorafenib (Pin vivo.
1 context sentence(design, population, supporting numbers)
Summary · context
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.
Show in the study text Report a problemFND-3627607001
03AnimalAnimal study (in vivo)Efficacy outcome
In an in vivo hepatocellular carcinoma model, pegvisomant overcame sorafenib resistance (P<0.0001).
In plain wordsIn an animal liver cancer model, pegvisomant overcame resistance to sorafenib.
Peptide
Pegvisomant
Outcome
DecreaseSorafenib resistance
Study
n: not reported in source
Sorafenib-resistant hepatocellular carcinoma in vivo model
Outcome group
Tumor growth · Cancer
Studied dose
Dose not stated
Source sentences
Summary
In addition, pegvisomant potentiated the effects of sorafenib (Pin vivo.
Show in the study text Report a problemFND-3627607002
04LabIn vitro (cells)Efficacy outcome
In hepatocellular carcinoma cells, GHR blockade with pegvisomant induced substantial inhibitory cellular effects.
In plain wordsIn cells from liver cancers, pegvisomant produced substantial inhibitory effects.
Peptide
Pegvisomant
Outcome
Direction not reportedInhibitory cellular effects
Study
n: not reported in source
Hepatocellular carcinoma cells
Outcome group
Tumor growth · Cancer
Studied dose
Dose not stated
Source sentences
Summary
Blockade of GHR signaling with siRNA or pegvisomant induced substantial inhibitory cellular effects in vitro.
1 context sentence(design, population, supporting numbers)
Summary · context
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.
Show in the study text Report a problemFND-3627607005
05LabOther designMechanism
In hepatocellular carcinoma experiments, pegvisomant decreased phosphorylation of downstream survival proteins, including JAK2, STAT3, STAT5, IRS-1, AKT, ERK, and IGF-IR.
In plain wordsIn lab tests, pegvisomant reduced phosphorylation of several survival proteins downstream of the growth hormone receptor.
Peptide
Pegvisomant
Outcome
DecreaseSurvival protein phosphorylation
Study
n: not reported in source
Hepatocellular carcinoma model, experimental setting not specified for this result
Outcome group
Receptor activity and mechanism · Cancer
Studied dose
Dose not stated
Source sentences
Summary
Mechanistically, pegvisomant decreased the phosphorylation of GHR downstream survival proteins including JAK2, STAT3, STAT5, IRS-1, AKT, ERK, and IGF-IR.
Show in the study text Report a problemFND-3627607003

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Version 2Current
28 Oct 2026, 02:03 UTC
Study results updated
Version 1
27 Oct 2026, 16:34 UTC
First added · source update from Europe PMC

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