Unmasking a new prognostic marker and therapeutic target from the GDNF-RET/PIT1/p14ARF/p53 pathway in acromegaly
| Autor: | Maria Suarez-Fariña, Pamela V. Lear, Javier Rodríguez-García, Miguel Chenlo, A. García-Allut, Cristina Álvarez-Escolá, Ramon Serramito, Angela R. Garcia-Rendueles, Clara V. Alvarez, Sihara Perez-Romero, José Manuel Cabezas-Agrícola, Rosa M. Alvarez-San Martin, E. Fernández-Rodríguez, Rocío Villar-Taibo, Ignacio Bernabeu, I.A. Rodríguez-Gómez |
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| Přispěvatelé: | UAM. Departamento de Medicina, Instituto de Investigación Sanitaria Hospital Universitario de La Paz (IdiPAZ), Universidade de Santiago de Compostela. Centro de Investigación en Medicina Molecular e Enfermidades Crónicas, Universidade de Santiago de Compostela. Departamento de Fisioloxía |
| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Research paper Pituitary tumors Apoptosis GFRA4 Vandetanib chemistry.chemical_compound 0302 clinical medicine Tumor Suppressor Protein p14ARF Glial cell line-derived neurotrophic factor biology Sunitinib Endoscopy surgery ARF General Medicine Sorafenib Prognosis Combined Modality Therapy Immunohistochemistry acromegalia Human pituitary cultures Treatment Outcome 030220 oncology & carcinogenesis Transcription Factor Pit-1 Lenvatinib Signal Transduction medicine.drug neoplasias hipofisarias Somatotropic cell Medicina Acromegalia y gigantismo hipofisario Models Biological General Biochemistry Genetics and Molecular Biology 03 medical and health sciences Acromegaly medicine Animals Humans Pituitary Neoplasms Glial Cell Line-Derived Neurotrophic Factor business.industry Gene Expression Profiling Somatotropinomas Proto-Oncogene Proteins c-ret medicine.disease Rats 030104 developmental biology Gene Expression Regulation chemistry SSA-resistance Mutation biology.protein Cancer research Tumor Suppressor Protein p53 business Biomarkers Tumores da glándula pituitaria |
| Zdroj: | Biblos-e Archivo. Repositorio Institucional de la UAM instname RUNA. Repositorio da Consellería de Sanidade e Sergas Servizo Galego de Saúde (SERGAS) Minerva. Repositorio Institucional de la Universidad de Santiago de Compostela |
| Popis: | 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 Investigacion (AEI) and Instituto Investigacion 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. |
| Databáze: | OpenAIRE |
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