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Growth Hormone Receptor Antagonist Markedly Improves Gemcitabine Response in a Mouse Xenograft Model of Human Pancreatic Cancer.
Basu, Reetobrata; Kulkarni, Prateek; Swegan, Deborah; Duran-Ortiz, Silvana; Ahmad, Arshad; Caggiano, Lydia J; Davis, Emily; Walsh, Christopher; Brenya, Edward; Koshal, Adeel; Brody, Rich; Sandbhor, Uday; Neggers, Sebastian J C M M; Kopchick, John J.
Afiliación
  • Basu R; Edison Biotechnology Institute, Ohio University, Athens, OH 45701, USA.
  • Kulkarni P; Diabetes Institute, Ohio University, Athens, OH 45701, USA.
  • Swegan D; Department of Biomedical Sciences, Heritage College of Osteopathic Medicine, Ohio University, Athens, OH 45701, USA.
  • Duran-Ortiz S; Edison Biotechnology Institute, Ohio University, Athens, OH 45701, USA.
  • Ahmad A; Molecular and Cellular Biology Program, Ohio University, Athens, OH 45701, USA.
  • Caggiano LJ; Department of Biological Sciences, Ohio University, Athens, OH 45701, USA.
  • Davis E; Edison Biotechnology Institute, Ohio University, Athens, OH 45701, USA.
  • Walsh C; Department of Biological Sciences, Ohio University, Athens, OH 45701, USA.
  • Brenya E; Edison Biotechnology Institute, Ohio University, Athens, OH 45701, USA.
  • Koshal A; Edison Biotechnology Institute, Ohio University, Athens, OH 45701, USA.
  • Brody R; Translational Biomedical Sciences Program, Ohio University, Athens, OH 45701, USA.
  • Sandbhor U; Edison Biotechnology Institute, Ohio University, Athens, OH 45701, USA.
  • Neggers SJCMM; Honors Tutorial College, Ohio University, Athens, OH 45701, USA.
  • Kopchick JJ; Edison Biotechnology Institute, Ohio University, Athens, OH 45701, USA.
Int J Mol Sci ; 25(13)2024 Jul 06.
Article en En | MEDLINE | ID: mdl-39000545
ABSTRACT
Chemotherapy treatment against pancreatic ductal adenocarcinoma (PDAC) is thwarted by tumoral activation of multiple therapy resistance pathways. The growth hormone (GH)-GH receptor (GHR) pair is a covert driver of multimodal therapy resistance in cancer and is overexpressed in PDAC tumors, yet the therapeutic potential of targeting the same has not been explored. Here, we report that GHR expression is a negative prognostic factor in patients with PDAC. Combinations of gemcitabine with different GHR antagonists (GHRAs) markedly improve therapeutic outcomes in nude mice xenografts. Employing cultured cells, mouse xenografts, and analyses of the human PDAC transcriptome, we identified that attenuation of the multidrug transporter and epithelial-to-mesenchymal transition programs in the tumors underlie the observed augmentation of chemotherapy efficacy by GHRAs. Moreover, in human PDAC patients, GHR expression strongly correlates with a gene signature of tumor promotion and immune evasion, which corroborate with that in syngeneic tumors in wild-type vs. GH transgenic mice. Overall, we found that GH action in PDAC promoted a therapy-refractory gene signature in vivo, which can be effectively attenuated by GHR antagonism. Our results collectively present a proof of concept toward considering GHR antagonists to improve chemotherapeutic outcomes in the highly chemoresistant PDAC.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Neoplasias Pancreáticas / Receptores de Somatotropina / Carcinoma Ductal Pancreático / Ensayos Antitumor por Modelo de Xenoinjerto / Desoxicitidina / Gemcitabina Límite: Animals / Female / Humans Idioma: En Revista: Int J Mol Sci Año: 2024 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Suiza
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Neoplasias Pancreáticas / Receptores de Somatotropina / Carcinoma Ductal Pancreático / Ensayos Antitumor por Modelo de Xenoinjerto / Desoxicitidina / Gemcitabina Límite: Animals / Female / Humans Idioma: En Revista: Int J Mol Sci Año: 2024 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Suiza