Caleiras, E. (Eduardo)
- Publications
- item.page.relationships.isContributorAdvisorOfPublication
- item.page.relationships.isContributorOfPublication
3 results
Search Results
Now showing 1 - 3 of 3
- Co-occurrence of mutations in NF1 and other susceptibility genes in pheochromocytoma and paraganglioma(2023) Leton, R. (Rocío); Maletta, F. (Francesca); Rapizzi, E. (Elena); Honrado, E. (Emiliano); Galvez, M.A. (Maria A.); Calatayud, M. (Maria); Fliedner, S.M.J. (Stephanie M.J.); Palacios, N. (Nuria); López-Fernández, A. (Adrià); Balbin, M. (Milagros); Eisenhofer, G. (Graeme); Lahera, M. (Marcos); Bancos, I. (Irina); Lider, S. (Sofia); Cascon, A. (Alberto); Caleiras, E. (Eduardo); Richter, S. (Susan); Gil, E. (Eduardo); Bechmann, N. (Nicole); Korpershoek, E. (Esther); Matías-Guiu, X. (Xavier); Canu, L. (Letizia); Lim, E.S. (Eugenie S.); Galofre, J.C. (Juan Carlos); Robledo, M. (Mercedes); Herrera-Martínez, A.D. (Aura D.); Mellid, S. (Sandra)IntroductionThe percentage of patients diagnosed with pheochromocytoma and paraganglioma (altogether PPGL) carrying known germline mutations in one of the over fifteen susceptibility genes identified to date has dramatically increased during the last two decades, accounting for up to 35-40% of PPGL patients. Moreover, the application of NGS to the diagnosis of PPGL detects unexpected co-occurrences of pathogenic allelic variants in different susceptibility genes. MethodsHerein we uncover several cases with dual mutations in NF1 and other PPGL genes by targeted sequencing. We studied the molecular characteristics of the tumours with co-occurrent mutations, using omic tools to gain insight into the role of these events in tumour development. ResultsAmongst 23 patients carrying germline NF1 mutations, targeted sequencing revealed additional pathogenic germline variants in DLST (n=1) and MDH2 (n=2), and two somatic mutations in H3-3A and PRKAR1A. Three additional patients, with somatic mutations in NF1 were found carrying germline pathogenic mutations in SDHB or DLST, and a somatic truncating mutation in ATRX. Two of the cases with dual germline mutations showed multiple pheochromocytomas or extra-adrenal paragangliomas - an extremely rare clinical finding in NF1 patients. Transcriptional and methylation profiling and metabolite assessment showed an intermediate signature to suggest that both variants had a pathological role in tumour development. DiscussionIn conclusion, mutations affecting genes involved in different pathways (pseudohypoxic and receptor tyrosine kinase signalling) co-occurring in the same patient could provide a selective advantage for the development of PPGL, and explain the variable expressivity and incomplete penetrance observed in some patients.
- A tumor-targeted trimeric 4-1BB-agonistic antibody induces potent anti-tumor immunity without systemic toxicity(2018) Pérez-Chacon, G. (Gema); Álvarez-Vallina, L. (Luis); Harwood, S.L. (Seandean Lykke); Muñoz, I.G. (Inés G.); Compte, M. (Marta); Merino, N. (Nekane); Zapata, J.M. (Juan M.); Núñez-Prado, N. (Natalia); Aznar, M.A. (María Ángela); Blanco, F.J. (Francisco J.); Erce-Llamazares, A. (Ainhoa); Cuesta, A.M. (Ángel M.); Sanz, L. (Laura); Mikkelsen, K. (Kasper); Martínez-Torrecuadrada, J. (Jorge); Melero, I. (Ignacio); Caleiras, E. (Eduardo); Tapia-Galisteo, A. (Alberto); Zonca, M. (Manuela); Serna, J.B. (Jorge Bernardino) de la; Lykkemark, S. (Simon); Navarro, R. (Rocío)The costimulation of immune cells using first-generation anti-4-1BB monoclonal antibodies (mAbs) has demonstrated anti-tumor activity in human trials. Further clinical development, however, is restricted by significant off-tumor toxicities associated with Fc gamma R interactions. Here, we have designed an Fc-free tumor-targeted 4-1BB-agonistic trimerbody, 1D8(N)/(C)EGa1, consisting of three anti-4-1BB single-chain variable fragments and three anti-EGFR single-domain antibodies positioned in an extended hexagonal conformation around the collagen XVIII homotrimerization domain. The1D8(N)/(C)EGa1 trimerbody demonstrated high-avidity binding to 4-1BB and EGFR and a potent in vitro costimulatory capacity in the presence of EGFR. The trimerbody rapidly accumulates in EGFR-positive tumors and exhibits anti-tumor activity similar to IgG-based 4-1BB-agonistic mAbs. Importantly, treatment with 1D8(N)/(C)EGa1 does not induce systemic inflammatory cytokine production or hepatotoxicity associated with IgG-based 4-1BB agonists. These results implicate Fc gamma R interactions in the 4-1BB-agonist-associated immune abnormalities, and promote the use of the non-canonical antibody presented in this work for safe and effective costimulatory strategies in cancer immunotherapy.
- Stratification of radiosensitive brain metastases based on an actionable S100A9/RAGE resistance mechanism(Nature Research, 2022) Cintado, E. (Elisa); Retana, D. (Diana); Troulé, K. (Kevin); Fustero-Torre, C. (Coral); Miarka, L. (Lauritz); Monteiro, C. (Cátia); Mazarico-Gallego, J. (José); Aristu-Mendioroz, J.J. (José Javier); Jiménez-Roldán, L. (Luis); Sepúlveda, J.M. (Juan Manuel); Trejo, J.L. (José Luis); Pérez-Núñez, A. (Ángel); Hegarty, A. (Aisling); Perea-García, M. (María); Tezanos, P. (Patricia); Siegfried, A. (Aurore); Muela, P. (Pablo); Priego, N. (Neibla); de Pablos-Aragoneses, A. (Ana); Caleiras, E. (Eduardo); Graña-Castro, O. (Osvaldo); Paz-Ares, L. (Luis); Moreno, L.M. (Luis Miguel); Ferrer, I. (Irene); González-León, P. (Pedro); García-Gómez, P. (Pedro); Suárez, R. (Rocío); Baena, P. (Patricia); Álvaro-Espinosa, L. (Laura); Esteban, O. (Olga)Whole-brain radiotherapy (WBRT) is the treatment backbone for many patients with brain metastasis; however, its efficacy in preventing disease progression and the associated toxicity have questioned the clinical impact of this approach and emphasized the need for alternative treatments. Given the limited therapeutic options available for these patients and the poor understand- ing of the molecular mechanisms underlying the resistance of metastatic lesions to WBRT, we sought to uncover actionable targets and biomarkers that could help to refine patient selection. Through an unbiased analysis of experimental in vivo models of brain metastasis resistant to WBRT, we identified activation of the S100A9–RAGE–NF-κB–JunB pathway in brain metastases as a potential mediator of resistance in this organ. Targeting this pathway genetically or pharmacologically was sufficient to revert the WBRT resistance and increase therapeutic benefits in vivo at lower doses of radiation. In patients with primary mela- noma, lung or breast adenocarcinoma developing brain metastasis, endogenous S100A9 levels in brain lesions correlated with clinical response to WBRT and underscored the potential of S100A9 levels in the blood as a noninvasive biomarker. Collectively, we provide a molecular framework to personalize WBRT and improve its efficacy through combination with a radiosensitizer that balances therapeutic benefit and toxicity.