Unmasking a new prognostic marker and therapeutic target from the GDNF-RET/PIT1/p14ARF/p53 pathway in acromegalyResearch in context
Background: Acromegaly is produced by excess growth hormone secreted by a pituitary adenoma of somatotroph cells (ACRO). First-line therapy, surgery and adjuvant therapy with somatostatin analogs, fails in 25% of patients. There is no predictive factor of resistance to therapy. New therapies are inv...
| Main Authors: | , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2019-05-01
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| Series: | EBioMedicine |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2352396419302415 |
| _version_ | 1818304735484051456 |
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| author | Miguel Chenlo Iria A. Rodriguez-Gomez Ramon Serramito Angela R. Garcia-Rendueles Rocío Villar-Taibo Eva Fernandez-Rodriguez Sihara Perez-Romero Maria Suarez-Fariña Alfredo Garcia-Allut Jose M. Cabezas-Agricola Javier Rodriguez-Garcia Pamela V. Lear Rosa M. Alvarez-San Martin Cristina Alvarez-Escola Ignacio Bernabeu Clara V. Alvarez |
| author_facet | Miguel Chenlo Iria A. Rodriguez-Gomez Ramon Serramito Angela R. Garcia-Rendueles Rocío Villar-Taibo Eva Fernandez-Rodriguez Sihara Perez-Romero Maria Suarez-Fariña Alfredo Garcia-Allut Jose M. Cabezas-Agricola Javier Rodriguez-Garcia Pamela V. Lear Rosa M. Alvarez-San Martin Cristina Alvarez-Escola Ignacio Bernabeu Clara V. Alvarez |
| author_sort | Miguel Chenlo |
| collection | DOAJ |
| description | Background: Acromegaly is produced by excess growth hormone secreted by a pituitary adenoma of somatotroph cells (ACRO). First-line therapy, surgery and adjuvant therapy with somatostatin analogs, fails in 25% of patients. There is no predictive factor of resistance to therapy. New therapies are investigated using few dispersed tumor cells in acute primary cultures in standard conditions where the cells do not grow, or using rat pituitary cell lines that do not maintain the full somatotroph phenotype. The RET/PIT1/p14ARF/p53 pathway regulates apoptosis in normal pituitary somatotrophs whereas the RET/GDNF pathway regulates survival, controlling PIT1 levels and blocking p14ARF (ARF) and p53 expression. Methods: We investigated these two RET pathways in a prospective series of 32 ACRO and 63 non-functioning pituitary adenomas (NFPA), studying quantitative RNA and protein gene expression for molecular-clinical correlations and how the RET pathway might be implicated in therapeutic success. Clinical data was collected during post-surgical follow-up. We also established new'humanized’ pituitary cultures, allowing 20 repeated passages and maintaining the pituitary secretory phenotype, and tested five multikinase inhibitors (TKI: Vandetanib, Lenvatinib, Sunitinib, Cabozantinib and Sorafenib) potentially able to act on the GDNF-induced RET dimerization/survival pathway. Antibody arrays investigated intracellular molecular pathways. Findings: In ACRO, there was specific enrichment of all genes in both RET pathways, especially GDNF. ARF and GFRA4 gene expression were found to be opposing predictors of response to first-line therapy. ARF cut-off levels, calculated categorizing by GNAS mutation, were predictive of good response (above) or resistance (below) to therapy months later. Sorafenib, through AMPK, blocked the GDNF/AKT survival action without altering the RET apoptotic pathway. Interpretation: Tumor ARF mRNA expression measured at the time of the surgery is a prognosis factor in acromegaly. The RET inhibitor, Sorafenib, is proposed as a potential treatment for resistant ACRO. Fund: This project was supported by national grants from Agencia Estatal de Investigación (AEI) and Instituto Investigación Carlos III, with participation of European FEDER funds, to IB (PI150056) and CVA (BFU2016-76973-R). It was also supported initially by a grant from the Investigator Initiated Research (IIR) Program (WI177773) and by a non-restricted Research Grant from Pfizer Foundation to IB. Some of the pituitary acromegaly samples were collected in the framework of the Spanish National Registry of Acromegaly (REMAH), partially supported by an unrestricted grant from Novartis to the Spanish Endocrine Association (SEEN).CVA is also supported from a grant of Medical Research Council UK MR/M018539/1. Keywords: Pituitary tumors, Somatotropinomas, Endoscopy surgery, Acromegaly, ARF, GFRA4, SSA-resistance, Human pituitary cultures, Sorafenib |
| first_indexed | 2024-12-13T06:15:25Z |
| format | Article |
| id | doaj.art-18978d90c30642d6a6cfc6c540bef848 |
| institution | Directory Open Access Journal |
| issn | 2352-3964 |
| language | English |
| last_indexed | 2024-12-13T06:15:25Z |
| publishDate | 2019-05-01 |
| publisher | Elsevier |
| record_format | Article |
| series | EBioMedicine |
| spelling | doaj.art-18978d90c30642d6a6cfc6c540bef8482022-12-21T23:56:59ZengElsevierEBioMedicine2352-39642019-05-0143537552Unmasking a new prognostic marker and therapeutic target from the GDNF-RET/PIT1/p14ARF/p53 pathway in acromegalyResearch in contextMiguel Chenlo0Iria A. Rodriguez-Gomez1Ramon Serramito2Angela R. Garcia-Rendueles3Rocío Villar-Taibo4Eva Fernandez-Rodriguez5Sihara Perez-Romero6Maria Suarez-Fariña7Alfredo Garcia-Allut8Jose M. Cabezas-Agricola9Javier Rodriguez-Garcia10Pamela V. Lear11Rosa M. Alvarez-San Martin12Cristina Alvarez-Escola13Ignacio Bernabeu14Clara V. Alvarez15Neoplasia & Endocrine Differentiation P0L5, Centro de Investigación en Medicina Molecular y Enfermedades Crónicas (CIMUS), University of Santiago de Compostela (USC), Spain; Instituto de Investigación Sanitaria (IDIS), Santiago de Compostela, SpainServicio de Endocrinología y Nutrición, Complejo Hospitalario Universitario de Santiago de Compostela (CHUS)-SERGAS, Santiago de Compostela, Spain; Servicio de Endocrinología y Nutrición, Hospital HM Modelo, A Coruña, Spain; Instituto de Investigación Sanitaria (IDIS), Santiago de Compostela, SpainServicio de Neurocirugía, Complejo Hospitalario Universitario de Santiago de Compostela (CHUS)-SERGAS, Santiago de Compostela, Spain; Instituto de Investigación Sanitaria (IDIS), Santiago de Compostela, SpainNeoplasia & Endocrine Differentiation P0L5, Centro de Investigación en Medicina Molecular y Enfermedades Crónicas (CIMUS), University of Santiago de Compostela (USC), Spain; Instituto de Investigación Sanitaria (IDIS), Santiago de Compostela, SpainServicio de Endocrinología y Nutrición, Complejo Hospitalario Universitario de Santiago de Compostela (CHUS)-SERGAS, Santiago de Compostela, Spain; Instituto de Investigación Sanitaria (IDIS), Santiago de Compostela, SpainServicio de Endocrinología y Nutrición, Complejo Hospitalario Universitario de Ourense, SpainNeoplasia & Endocrine Differentiation P0L5, Centro de Investigación en Medicina Molecular y Enfermedades Crónicas (CIMUS), University of Santiago de Compostela (USC), Spain; Instituto de Investigación Sanitaria (IDIS), Santiago de Compostela, SpainNeoplasia & Endocrine Differentiation P0L5, Centro de Investigación en Medicina Molecular y Enfermedades Crónicas (CIMUS), University of Santiago de Compostela (USC), Spain; Instituto de Investigación Sanitaria (IDIS), Santiago de Compostela, SpainServicio de Neurocirugía, Complejo Hospitalario Universitario de Santiago de Compostela (CHUS)-SERGAS, Santiago de Compostela, Spain; Instituto de Investigación Sanitaria (IDIS), Santiago de Compostela, SpainServicio de Endocrinología y Nutrición, Complejo Hospitalario Universitario de Santiago de Compostela (CHUS)-SERGAS, Santiago de Compostela, Spain; Instituto de Investigación Sanitaria (IDIS), Santiago de Compostela, SpainServicio de Análisis Clínicos, Complejo Hospitalario Universitario de Santiago de Compostela (CHUS)-SERGAS, Santiago de Compostela, Spain; Instituto de Investigación Sanitaria (IDIS), Santiago de Compostela, SpainDepartment of Physiology, Anatomy and Genetics, Oxford University, Oxford, United KingdomServicio de Endocrinología y Nutrición, Complejo Asistencial Universitario de Leon, SpainServicio de Endocrinología y Nutrición, Hospital Universitario La Paz, Madrid, SpainServicio de Endocrinología y Nutrición, Complejo Hospitalario Universitario de Santiago de Compostela (CHUS)-SERGAS, Santiago de Compostela, Spain; Instituto de Investigación Sanitaria (IDIS), Santiago de Compostela, Spain; Correspondence to: Ignacio Bernabeu, Servicio de Endocrinologia y Nutrición, Complejo Hospitalario Universitario de Santiago de Compostela (CHUS)-SERGAS, 15706 Santiago de Compostela, Spain.Neoplasia & Endocrine Differentiation P0L5, Centro de Investigación en Medicina Molecular y Enfermedades Crónicas (CIMUS), University of Santiago de Compostela (USC), Spain; Instituto de Investigación Sanitaria (IDIS), Santiago de Compostela, Spain; Correspondence to: Clara V Alvarez, Neoplasia & Endocrine Differentiation P0L5, Centro de Investigación en Medicina Molecular y Enfermedades Crónicas (CIMUS), Av Barcelona s/n, 15782 Santiago de Compostela, Spain.Background: Acromegaly is produced by excess growth hormone secreted by a pituitary adenoma of somatotroph cells (ACRO). First-line therapy, surgery and adjuvant therapy with somatostatin analogs, fails in 25% of patients. There is no predictive factor of resistance to therapy. New therapies are investigated using few dispersed tumor cells in acute primary cultures in standard conditions where the cells do not grow, or using rat pituitary cell lines that do not maintain the full somatotroph phenotype. The RET/PIT1/p14ARF/p53 pathway regulates apoptosis in normal pituitary somatotrophs whereas the RET/GDNF pathway regulates survival, controlling PIT1 levels and blocking p14ARF (ARF) and p53 expression. Methods: We investigated these two RET pathways in a prospective series of 32 ACRO and 63 non-functioning pituitary adenomas (NFPA), studying quantitative RNA and protein gene expression for molecular-clinical correlations and how the RET pathway might be implicated in therapeutic success. Clinical data was collected during post-surgical follow-up. We also established new'humanized’ pituitary cultures, allowing 20 repeated passages and maintaining the pituitary secretory phenotype, and tested five multikinase inhibitors (TKI: Vandetanib, Lenvatinib, Sunitinib, Cabozantinib and Sorafenib) potentially able to act on the GDNF-induced RET dimerization/survival pathway. Antibody arrays investigated intracellular molecular pathways. Findings: In ACRO, there was specific enrichment of all genes in both RET pathways, especially GDNF. ARF and GFRA4 gene expression were found to be opposing predictors of response to first-line therapy. ARF cut-off levels, calculated categorizing by GNAS mutation, were predictive of good response (above) or resistance (below) to therapy months later. Sorafenib, through AMPK, blocked the GDNF/AKT survival action without altering the RET apoptotic pathway. Interpretation: Tumor ARF mRNA expression measured at the time of the surgery is a prognosis factor in acromegaly. The RET inhibitor, Sorafenib, is proposed as a potential treatment for resistant ACRO. Fund: This project was supported by national grants from Agencia Estatal de Investigación (AEI) and Instituto Investigación Carlos III, with participation of European FEDER funds, to IB (PI150056) and CVA (BFU2016-76973-R). It was also supported initially by a grant from the Investigator Initiated Research (IIR) Program (WI177773) and by a non-restricted Research Grant from Pfizer Foundation to IB. Some of the pituitary acromegaly samples were collected in the framework of the Spanish National Registry of Acromegaly (REMAH), partially supported by an unrestricted grant from Novartis to the Spanish Endocrine Association (SEEN).CVA is also supported from a grant of Medical Research Council UK MR/M018539/1. Keywords: Pituitary tumors, Somatotropinomas, Endoscopy surgery, Acromegaly, ARF, GFRA4, SSA-resistance, Human pituitary cultures, Sorafenibhttp://www.sciencedirect.com/science/article/pii/S2352396419302415 |
| spellingShingle | Miguel Chenlo Iria A. Rodriguez-Gomez Ramon Serramito Angela R. Garcia-Rendueles Rocío Villar-Taibo Eva Fernandez-Rodriguez Sihara Perez-Romero Maria Suarez-Fariña Alfredo Garcia-Allut Jose M. Cabezas-Agricola Javier Rodriguez-Garcia Pamela V. Lear Rosa M. Alvarez-San Martin Cristina Alvarez-Escola Ignacio Bernabeu Clara V. Alvarez Unmasking a new prognostic marker and therapeutic target from the GDNF-RET/PIT1/p14ARF/p53 pathway in acromegalyResearch in context EBioMedicine |
| title | Unmasking a new prognostic marker and therapeutic target from the GDNF-RET/PIT1/p14ARF/p53 pathway in acromegalyResearch in context |
| title_full | Unmasking a new prognostic marker and therapeutic target from the GDNF-RET/PIT1/p14ARF/p53 pathway in acromegalyResearch in context |
| title_fullStr | Unmasking a new prognostic marker and therapeutic target from the GDNF-RET/PIT1/p14ARF/p53 pathway in acromegalyResearch in context |
| title_full_unstemmed | Unmasking a new prognostic marker and therapeutic target from the GDNF-RET/PIT1/p14ARF/p53 pathway in acromegalyResearch in context |
| title_short | Unmasking a new prognostic marker and therapeutic target from the GDNF-RET/PIT1/p14ARF/p53 pathway in acromegalyResearch in context |
| title_sort | unmasking a new prognostic marker and therapeutic target from the gdnf ret pit1 p14arf p53 pathway in acromegalyresearch in context |
| url | http://www.sciencedirect.com/science/article/pii/S2352396419302415 |
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