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

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 systemi...

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Autores principales: Kaseb, Ahmed O., Haque, Abedul, Vishwamitra, Deeksha, Hassan, Manal M., Xiao, Lianchun, George, Bhawana, Sahu, Vishal, Mohamed, Yehia I., Carmagnani Pestana, Roberto, Lombardo, Jamie Lynne, Avritscher, Rony, Yao, James C., Wolff, Robert A., Rashid, Asif, Morris, Jeffrey S., Amin, Hesham M.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9582251/
https://www.ncbi.nlm.nih.gov/pubmed/36276070
http://dx.doi.org/10.3389/fonc.2022.986305
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author Kaseb, Ahmed O.
Haque, Abedul
Vishwamitra, Deeksha
Hassan, Manal M.
Xiao, Lianchun
George, Bhawana
Sahu, Vishal
Mohamed, Yehia I.
Carmagnani Pestana, Roberto
Lombardo, Jamie Lynne
Avritscher, Rony
Yao, James C.
Wolff, Robert A.
Rashid, Asif
Morris, Jeffrey S.
Amin, Hesham M.
author_facet Kaseb, Ahmed O.
Haque, Abedul
Vishwamitra, Deeksha
Hassan, Manal M.
Xiao, Lianchun
George, Bhawana
Sahu, Vishal
Mohamed, Yehia I.
Carmagnani Pestana, Roberto
Lombardo, Jamie Lynne
Avritscher, Rony
Yao, James C.
Wolff, Robert A.
Rashid, Asif
Morris, Jeffrey S.
Amin, Hesham M.
author_sort Kaseb, Ahmed O.
collection PubMed
description 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.
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spelling pubmed-95822512022-10-21 Blockade of growth hormone receptor signaling by using pegvisomant: A functional therapeutic strategy in hepatocellular carcinoma Kaseb, Ahmed O. Haque, Abedul Vishwamitra, Deeksha Hassan, Manal M. Xiao, Lianchun George, Bhawana Sahu, Vishal Mohamed, Yehia I. Carmagnani Pestana, Roberto Lombardo, Jamie Lynne Avritscher, Rony Yao, James C. Wolff, Robert A. Rashid, Asif Morris, Jeffrey S. Amin, Hesham M. Front Oncol Oncology 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. Frontiers Media S.A. 2022-10-06 /pmc/articles/PMC9582251/ /pubmed/36276070 http://dx.doi.org/10.3389/fonc.2022.986305 Text en Copyright © 2022 Kaseb, Haque, Vishwamitra, Hassan, Xiao, George, Sahu, Mohamed, Carmagnani Pestana, Lombardo, Avritscher, Yao, Wolff, Rashid, Morris and Amin https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Oncology
Kaseb, Ahmed O.
Haque, Abedul
Vishwamitra, Deeksha
Hassan, Manal M.
Xiao, Lianchun
George, Bhawana
Sahu, Vishal
Mohamed, Yehia I.
Carmagnani Pestana, Roberto
Lombardo, Jamie Lynne
Avritscher, Rony
Yao, James C.
Wolff, Robert A.
Rashid, Asif
Morris, Jeffrey S.
Amin, Hesham M.
Blockade of growth hormone receptor signaling by using pegvisomant: A functional therapeutic strategy in hepatocellular carcinoma
title Blockade of growth hormone receptor signaling by using pegvisomant: A functional therapeutic strategy in hepatocellular carcinoma
title_full Blockade of growth hormone receptor signaling by using pegvisomant: A functional therapeutic strategy in hepatocellular carcinoma
title_fullStr Blockade of growth hormone receptor signaling by using pegvisomant: A functional therapeutic strategy in hepatocellular carcinoma
title_full_unstemmed Blockade of growth hormone receptor signaling by using pegvisomant: A functional therapeutic strategy in hepatocellular carcinoma
title_short Blockade of growth hormone receptor signaling by using pegvisomant: A functional therapeutic strategy in hepatocellular carcinoma
title_sort blockade of growth hormone receptor signaling by using pegvisomant: a functional therapeutic strategy in hepatocellular carcinoma
topic Oncology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9582251/
https://www.ncbi.nlm.nih.gov/pubmed/36276070
http://dx.doi.org/10.3389/fonc.2022.986305
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