Growth Hormone Receptor Antagonist Markedly Improves Gemcitabine Response in a Mouse Xenograft Model of Human Pancreatic Cancer

How to cite: Basu, R.; Kulkarni, P.; Swegan, D.; Duran-Ortiz, S.; Ahmad, A.; Caggiano, L. J.; Davis, E.; Walsh, C.; Brenya, E.; Koshal, A.; Brody, R.; Sandbhor, U.; Neggers, S. J.; Kopchick, J. J. Growth Hormone Receptor Antagonist Markedly Improves Gemcitabine Response in a Mouse Xenograft Model of Human Pancreatic Cancer. Preprints 2024, 2024050782. https://doi.org/10.20944/preprints202405.0782.v1 Basu, R.; Kulkarni, P.; Swegan, D.; Duran-Ortiz, S.; Ahmad, A.; Caggiano, L. J.; Davis, E.; Walsh, C.; Brenya, E.; Koshal, A.; Brody, R.; Sandbhor, U.; Neggers, S. J.; Kopchick, J. J. Growth Hormone Receptor Antagonist Markedly Improves Gemcitabine Response in a Mouse Xenograft Model of Human Pancreatic Cancer. Preprints 2024, 2024050782. https://doi.org/10.20944/preprints202405.0782.v1

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MDPI and ACS Style

Basu, R.; Kulkarni, P.; Swegan, D.; Duran-Ortiz, S.; Ahmad, A.; Caggiano, L. J.; Davis, E.; Walsh, C.; Brenya, E.; Koshal, A.; Brody, R.; Sandbhor, U.; Neggers, S. J.; Kopchick, J. J. Growth Hormone Receptor Antagonist Markedly Improves Gemcitabine Response in a Mouse Xenograft Model of Human Pancreatic Cancer. Preprints 2024, 2024050782. https://doi.org/10.20944/preprints202405.0782.v1

APA Style

Basu, R., Kulkarni, P., Swegan, D., Duran-Ortiz, S., Ahmad, A., Caggiano, L. J., Davis, E., Walsh, C., Brenya, E., Koshal, A., Brody, R., Sandbhor, U., Neggers, S. J., & Kopchick, J. J. (2024). Growth Hormone Receptor Antagonist Markedly Improves Gemcitabine Response in a Mouse Xenograft Model of Human Pancreatic Cancer. Preprints. https://doi.org/10.20944/preprints202405.0782.v1

Chicago/Turabian Style

Basu, R., Sebastian J.C.M.M Neggers and John J Kopchick. 2024 "Growth Hormone Receptor Antagonist Markedly Improves Gemcitabine Response in a Mouse Xenograft Model of Human Pancreatic Cancer" Preprints. https://doi.org/10.20944/preprints202405.0782.v1

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 towards considering GHR antagonist to improve chemotherapeutic outcome in the highly chemoresistant PDAC.

Keywords

Pancreatic cancer; pancreatic ductal adenocarcinoma; gemcitabine; growth hormone (GH); GH receptor (GHR); GHR antagonist; insulin-like growth factor 1 (IGF1);adjuvant; chemotherapy; chemoresistance

Subject

Biology and Life Sciences, Biochemistry and Molecular Biology

Copyright: This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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