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Orthoxenografts of Testicular Germ Cell Tumors Demonstrate Genomic Changes Associated with Cisplatin Resistance and Identify PDMP As a Resensitizing Agent Josep M

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Orthoxenografts of Testicular Germ Cell Tumors Demonstrate Genomic Changes Associated with Cisplatin Resistance and Identify PDMP As a Resensitizing Agent Josep M Published OnlineFirst April 4, 2018; DOI: 10.1158/1078-0432.CCR-17-1898 Cancer Therapy: Preclinical Clinical Cancer Research Orthoxenografts of Testicular Germ Cell Tumors Demonstrate Genomic Changes Associated with Cisplatin Resistance and Identify PDMP as a Resensitizing Agent Josep M. Piulats1,2, August Vidal3,4, Francisco J García-Rodríguez1,8, Clara Munoz~ 1, Marga Nadal1, Catia Moutinho5, María Martínez-Iniesta1, Josefina Mora6, Agnes Figueras1, Elisabet Guino7, Laura Padulles 1, Alvaro Aytes 1, David G. Molleví1, Sara Puertas1, Carmen Martínez-Fernandez 8, Wilmar Castillo1, Merce Juliachs1, Victor Moreno7, Purificacion Munoz~ 5, Milica Stefanovic9, Miguel A. Pujana1, Enric Condom3, Manel Esteller5, Josep R. Germa2, Gabriel Capella1, Lourdes Farre1,10,11, Albert Morales7, Francesc Vinals~ 1,12, Xavier García-del-Muro2, Julian Ceron 8,13, and Alberto Villanueva1,13,4 Abstract Purpose: To investigate the genetic basis of cisplatin resistance metastatic germ cell tumors. We studied the expression profile as efficacy of cisplatin-based chemotherapy in the treatment of of the 60 genes located at that genomic region. POLE3 and distinct malignancies is often hampered by intrinsic or acquired AKNA were the only two genes deregulated in resistant tumors drug resistance of tumor cells. harboring the 9q32-q33.1 gain. Moreover, other four genes Experimental Design: We produced 14 orthoxenograft trans- (GCS, ZNF883, CTR1, and FLJ31713) were deregulated in planting human nonseminomatous testicular germ cell tumors all five resistant tumors independently of the 9q32-q33.1 (TGCT) in mice, keeping the primary tumor features in terms of amplification. RT-PCRs in tumors and functional analyses genotype, phenotype, and sensitivity to cisplatin. Chromosomal in Caenorhabditis elegans (C. elegans) indicate that the influence and genetic alterations were evaluated in matched cisplatin-sen- of 9q32-q33.1 genes in cisplatin resistance can be driven sitive and their counterpart orthoxenografts that developed resis- by either up- or downregulation. We focused on glucosylcer- tance to cisplatin in nude mice. amide synthase (GCS) to demonstrate that the GCS inhib- Results: Comparative genomic hybridization analyses of four itor DL-threo-PDMP resensitizes cisplatin-resistant germline- matched orthoxenografts identified recurrent chromosomal derived orthoxenografts to cisplatin. rearrangements across cisplatin-resistant tumors in three of Conclusions: Orthoxenografts can be used preclinically not them, showing gains at 9q32-q33.1 region. We found a clinical only to test the efficiency of drugs but also to identify prognosis correlation between the presence of 9q32-q33.1 gains in cis- markers and gene alterations acting as drivers of the acquired platin-refractory patients and poorer overall survival (OS) in cisplatin resistance. Clin Cancer Res; 1–12. Ó2018 AACR. 1Program Against Cancer Therapeutic Resistance (ProCURE), Catalan Institute L'Hospitalet de Llobregat, Barcelona, Spain. 13C. elegans Core Facilty-IDIBELL, of Oncology (ICO), Bellvitge Institute for Biomedical Research (IDIBELL), Barcelona, Spain. Oncobell Program, L'Hospitalet del Llobregat, Barcelona, Catalonia, Spain. 2Department of Medical Oncology, Catalan Institute of Oncology (IDIBELL), Note: Supplementary data for this article are available at Clinical Cancer Barcelona, Spain. 3Department of Pathology, Hospital Universitari de Bellvitge Research Online (http://clincancerres.aacrjournals.org/). (IDIBELL), CIBERONC, Barcelona, Spain. 4Xenopat S.L., Business Bioincubator, Bellvitge Health Science Campus, L'Hospitalet de Llobregat, Barcelona, Spain. J.M. Piulats and A. Vidal contributed equally to this article. 5Cancer Epigenetics and Cell Biology Program (PEBC), Catalan Institute of Corresponding Authors: Alberto Villanueva, Catalan Institute of Oncology Oncology (IDIBELL), Barcelona, Spain. 6Department of Biochemistry, Hospital 7 (ICO/IDIBELL), Hospital Duran i Reynals, 3a planta - Gran Via de l'Hospitalet, de Sant Pau, Barcelona, Spain. Bioinformatic Unit, Catalan Institute of Oncology 199, L'Hospitalet de Llobregat, Barcelona 08908, Spain. Phone: 349-3260-7952; (IDIBELL), Barcelona, Spain. 8Modelling Human Diseases in C. elegans. Genes, Fax: 349-3260-7466; E-mail: [email protected]; and Julian Ceron, Disease and Therapy Program (IDIBELL), Barcelona, Spain. 9Department of Cell Bellvitge Institute for Biomedical Research (IDIBELL),Hospital Duran i Reynals, Death and Proliferation, Instituto de Investigaciones Biomedicas de Barcelona 3a planta - Gran Via de l'Hospitalet, 199, L'Hospitalet de Llobregat, Barcelona (IIBB-CSIC), IDIBAPS, L'Hospitalet de Llobregat, Barcelona, Catalonia, Spain. 08907, Spain. Phone: 349-3260-7287; [email protected]. 10Laboratory of Experimental Pathology (LAPEX), Goncalo¸ Moniz Research Center, Oswaldo Cruz Foundation (CPQGM/FIOCRUZ), Salvador, Bahia, Brazil. doi: 10.1158/1078-0432.CCR-17-1898 11Institute of Science and Technology of Tropical Diseases (INCT/DT), Salvador, Brazil. 12Departament de Ciencies Fisiologiques II, Universitat de Barcelona, Ó2018 American Association for Cancer Research. www.aacrjournals.org OF1 Downloaded from clincancerres.aacrjournals.org on October 1, 2021. © 2018 American Association for Cancer Research. Published OnlineFirst April 4, 2018; DOI: 10.1158/1078-0432.CCR-17-1898 Piulats et al. Translational Relevance Materials and Methods Human primary TGCT implantation and perpetuation in Cisplatin-based cytotoxic chemotherapy is the mainstay nude mice of the treatment of several types of neoplasias. The acquired To generate the collection of TGCT orthoxenografts, fresh resistance is a major clinical limitation for patient's survival. surgical specimens of 62 human GCTs were implanted in nude Orthoxenografts are the most advanced ex vivo platforms to mice. Twenty-two tumors were classified as pure SEs and 40 as investigate the efficiency of drugs in a personalized manner, NSE (21 as pure and 19 as mixed tumors containing different but in this study, we also demonstrated other valuable tools proportions of SE and NSE components). From the 40 NSEs, to identify prognosis markers and novel resensitizing ther- 14 tumors were perpetuated (35%), 10 derived from pure NSEs apeutic approaches for the treatment of cisplatin-refractory [three choriocarcinomas (CH), four embryonal carcinomas (EC), tumors. As proof-of-principle, in this study we validate our three yolk sac tumors (YS)], and four from mixed primary tumors. approach demonstrating that presence of the 9q32-q33.1 Five orthoxenografts were derived from several extragonadal gain is associated with poor risk defined by shorter overall tumor locations, and in four cases from patients treated previ- survival (OS) and that genetic or pharmacologic inhibition ously with cisplatin-based chemotherapy (Supplementary Table of glucosylceramide synthase (GCS) activity is efficient to S1). None of the 22 implanted pure gonadal seminomas (SE) resensitize testicular and epithelial ovarian tumors refrac- grew in nude mice. Of the mixed tumors, comprising both SE and tory to cisplatin. NSE components, only the NSEs grew in mice. Orthotopic implantation procedure of human tumors was performed as previously reported by our group (21) and briefly described in the Supplementary Data. IHC characterization is also described Introduction in the Supplementary Data. All patients gave written consent to Testicular germ cell tumors (TGCT) of adolescent and young participate in the study. The Institutional Ethics Committees adults are the most common malignancy in young men (1–3). approved the study protocol, and the animal experimental design They can be classified as seminomas (SE; originated in epithe- was approved by the IDIBELL animal facility committee (AAALAC – lium of the seminiferous tubules), which represent around 40% Unit 1155). All experiments were performed in accordance with of cases, and nonseminomas (NSE; 60%). Seminomas are radio- the guidelines for Ethical Conduct in the Care and Use of Animals and chemo-sensitive tumors highly curable at all stages. With as stated in The International Guiding Principles for Biomedical the exception of teratomas, NSEs are also highly sensitive to Research Involving Animals, developed by the Council for Inter- cisplatin-based chemotherapy and, when combined with sur- national Organizations of Medical Sciences. gery, patients achieve high cure rates (4). In contrast with most advanced solid tumors, approximately 80%–90% of metastatic Generation in mice of refractory engrafted NSEs to cisplatin TGCTs will achieve complete cure after standard doses of treatment cisplatin (CDDP) chemotherapy (4). Nevertheless, 10%–15% Five selected engrafted tumors, TGT1X, TGT12X, TGT21XB, of patients die due to cisplatin refractoriness and the absence of TGT34X and TGT38X, from patients without prior exposure alternative effective resensitizing therapies (5–7). Such high to cisplatin, were allowed to grow until intraabdominal palpable success in treating advanced testicular cancer has limited the masses were noted. Animals were administered with cisplatin number of studies addressing the treatment failure in refractory intravenously at a dose of 2 mg/kg for 3 consecutive weeks (days 0, patients (8, 9). 7, and 14; cycle #1 of treatment). Post-cisplatin relapse, tumors In TGCTs, cisplatin resistance has been attributed to diverse were harvested, prepared as described previously and engrafted in fi cellular mechanisms (10–12), although the molecular details new animals. This process
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