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https://www.arca.fiocruz.br/handle/icict/31701
ORTHOXENOGRAFTS OF TESTICULAR GERM CELL TUMORS DEMONSTRATE GENOMIC CHANGES ASSOCIATED WITH CISPLATIN RESISTANCE AND IDENTIFY PDMP AS A RESENSITIZING AGENT
Neoplasias testiculares
Glicosilceramida
Resistência a drogas
Quimioterapia
Células germinativas
Animais
Testicular Neoplasms
Glucosylceramide
Drug Resistance
Chemotherapy
Germ Cells
Animals
Author
Piulats, Josep M.
Vidal, August
Rodríguez, Francisco J. García
Muñoz, Clara
Nadal, Marga
Moutinho, Catia
Iniesta, María Martínez
Mora, Josefina
Figueras, Agnés
Guinó, Elisabet
Padullés, Laura
Aytés, Àlvaro
Molleví, David G.
Puertas, Sara
Fernández, Carmen Martínez
Castillo, Wilmar
Juliachs, Merce
Moreno, Victor
Muñoz, Purificación
Stefanovic, Milica
Pujana, Miguel A.
Condom, Enric
Esteller, Manel
Germà, Josep R.
Capella, Gabriel
Farré, Maria de Lourdes Vallve
Morales, Albert
Viñals, Francesc
García-Del-Muro, Xavier
Cerón, Julián
Villanueva, Alberto
Vidal, August
Rodríguez, Francisco J. García
Muñoz, Clara
Nadal, Marga
Moutinho, Catia
Iniesta, María Martínez
Mora, Josefina
Figueras, Agnés
Guinó, Elisabet
Padullés, Laura
Aytés, Àlvaro
Molleví, David G.
Puertas, Sara
Fernández, Carmen Martínez
Castillo, Wilmar
Juliachs, Merce
Moreno, Victor
Muñoz, Purificación
Stefanovic, Milica
Pujana, Miguel A.
Condom, Enric
Esteller, Manel
Germà, Josep R.
Capella, Gabriel
Farré, Maria de Lourdes Vallve
Morales, Albert
Viñals, Francesc
García-Del-Muro, Xavier
Cerón, Julián
Villanueva, Alberto
Affilliation
Fundação Oswaldo Cruz. Instituto Gonçalo Moniz. Salvador, BA, Brasil.
Multipla - ver em Notas
Multipla - ver em Notas
Abstract
Purpose: To investigate the genetic basis of cisplatin resistance as efficacy of cisplatin-based chemotherapy in the treatment of distinct malignancies is often hampered by intrinsic or acquired drug resistance of tumor cells.Experimental Design: We produced 14 orthoxenograft transplanting human nonseminomatous testicular germ cell tumors (TGCT) in mice, keeping the primary tumor features in terms of genotype, phenotype, and sensitivity to cisplatin. Chromosomal and genetic alterations were evaluated in matched cisplatin-sensitive and their counterpart orthoxenografts that developed resistance to cisplatin in nude mice.Results: Comparative genomic hybridization analyses of four matched orthoxenografts identified recurrent chromosomal rearrangements across cisplatin-resistant tumors in three of them, showing gains at 9q32-q33.1 region. We found a clinical correlation between the presence of 9q32-q33.1 gains in cisplatin-refractory patients and poorer overall survival (OS) in metastatic germ cell tumors. We studied the expression profile of the 60 genes located at that genomic region. POLE3 and AKNA were the only two genes deregulated in resistant tumors harboring the 9q32-q33.1 gain. Moreover, other four genes (GCS, ZNF883, CTR1, and FLJ31713) were deregulated in all five resistant tumors independently of the 9q32-q33.1 amplification. RT-PCRs in tumors and functional analyses in Caenorhabditis elegans (C. elegans) indicate that the influence of 9q32-q33.1 genes in cisplatin resistance can be driven by either up- or downregulation. We focused on glucosylceramide synthase (GCS) to demonstrate that the GCS inhibitor DL-threo-PDMP resensitizes cisplatin-resistant germline-derived orthoxenografts to cisplatin.Conclusions: Orthoxenografts can be used preclinically not only to test the efficiency of drugs but also to identify prognosis markers and gene alterations acting as drivers of the acquired cisplatin resistance. Clin Cancer Res; 24(15); 3755-66. ©2018 AACR.
Keywords in Portuguese
TumoresNeoplasias testiculares
Glicosilceramida
Resistência a drogas
Quimioterapia
Células germinativas
Animais
Keywords
TumorsTesticular Neoplasms
Glucosylceramide
Drug Resistance
Chemotherapy
Germ Cells
Animals
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