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Orthoxenografts of Testicular Germ Cell Tumors Demonstrate Genomic 2 Changes Associated with Cisplatin Resistance and Identify PDMP As a Re- 3 Sensitizing Agent

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Orthoxenografts of Testicular Germ Cell Tumors Demonstrate Genomic 2 Changes Associated with Cisplatin Resistance and Identify PDMP As a Re- 3 Sensitizing Agent Author Manuscript Published OnlineFirst on April 4, 2018; DOI: 10.1158/1078-0432.CCR-17-1898 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. 1 Orthoxenografts of testicular germ cell tumors demonstrate genomic 2 changes associated with cisplatin resistance and identify PDMP as a re- 3 sensitizing agent 1,2& 3,12& 1 1 4 Josep M. Piulats , August Vidal , Francisco J García-Rodríguez , Clara Muñoz , Marga 5 Nadal 1, Catia Moutinho 4, María Martínez-Iniesta 1, Josefina Mora 5, Agnés Figueras 1, Elisabet 6 Guinó 6, Laura Padullés 1, Àlvaro Aytés 1, David G. Molleví 1, Sara Puertas 1, Carmen Martínez- 7 Fernández8, Wilmar Castillo 1, Merce Juliachs 1, Victor Moreno 6, Purificación Muñoz 4, Milica 7 1 3 4 2 8 Stefanovic , Miguel A. Pujana , Enric Condom , Manel Esteller , Josep R. Germà , Gabriel 1 1,10 7 1,9 2 9 Capella , Lourdes Farré , Albert Morales , Francesc Viñals , Xavier García-del-Muro , 10 Julián Cerón 8,11 and Alberto Villanueva 1,11,12. 11 1. Program Against Cancer Therapeutic Resistance (ProCURE), Catalan Institute of Oncology (ICO), 12 Bellvitge Institute for Biomedical Research (IDIBELL), Oncobell Program, L’Hospitalet del 13 Llobregat, Barcelona 08908, Catalonia, Spain. 14 2. Department of Medical Oncology, Catalan Institute of Oncology – IDIBELL. 15 3. Department of Pathology, Hospital Universitari de Bellvitge – IDIBELL. CIBERONC. 16 4. Cancer Epigenetics and Cell Biology Program (PEBC), Catalan Institute of Oncology –IDIBELL 17 5. Department of Biochemistry, Hospital de Sant Pau, 08025 Barcelona, Spain. 18 6. Bioinformatic Unit, Catalan Institute of Oncology – IDIBELL. 19 7. Department of Cell Death and Proliferation, Instituto de Investigaciones Biomédicas de Barcelona 20 (IIBB-CSIC), IDIBAPS, Barcelona, Catalonia, Spain. 21 8. Modelling Human Diseases in C. elegans. Genes, Disease and Therapy Program – IDIBELL. 22 9. Departament de Ciències Fisiològiques II, Universitat de Barcelona, Avda Feixa Llarga S/N 08907 23 L'Hospitalet de Llobregat, Barcelona, Spain. 24 10. Laboratory of Experimental Pathology (LAPEX), Gonçalo Moniz Research Center, Oswaldo Cruz 25 Foundation (CPQGM/FIOCRUZ), Salvador, Bahia, Brazil; National Institute of Science and 26 Technology of Tropical Diseases (INCT/DT), Salvador, Brazil. 27 11. C. elegans Core Facilty-IDIBELL. 28 12. Xenopat S.L., Business Bioincubator, Bellvitge Health Science Campus, 08907 L’Hospitalet de 29 Llobregat, Barcelona, Spain. 30 31 Running title: Orthoxenografts to identify targets for cisplatin resistance 32 Key words: Germ cell tumor, orthoxenografts, cisplatin resistance, glucosylceramide synthase, 33 PDMP. 34 Additional information: 35 & Authors contributed equally to this work 36 Financial support: Several authors are grateful recipients of predoctoral fellowships: JMP from the 37 AECC and FJG-R from the Instituto De Salut Carlos III (ISCIII). This study was supported by grants 38 from the Spanish Ministry of Economy and Competitiveness (SAF2002-02265 and FIS: BFU2007- 39 67123; PI10-0222, PI13-01339, PI16/01898) to AV, PI15-00895 to JC, SAF2013-46063R to FV, 40 PI030264 to XGM, Fundació La Marató TV3 (051430) to FV and XGM, Generalitat de Catalunya 41 (2014SGR364) to AV and FV, FIS09/0059 to AM, confunded by FEDER funds/ European 42 Regional Development Fund (ERDF)-a way to Build Europe. A. Vidal received a BAE11/00073 43 grant. 44 Corresponding authors: Julian Ceron PhD. Genes, Disease and Therapy Program – IDIBELL. Avda 45 Gran Via s/n km 2.7 L’Hospitalet de Llobregat, 08907 Barcelona, Spain. Phone: 34-93 260 7251; 46 Fax: 34-93 260 7466; [email protected]. Alberto Villanueva PhD. Laboratory of Translational 47 Research. ICO-IDIBELL, Hospital Duran i Reynals, Avda Gran Via s/n km 2.7 L’Hospitalet de 48 Llobregat, 08907 Barcelona, Spain. Phone: 34-93260 7952; Fax: 34-93 260 7466; 49 [email protected] 1 Downloaded from clincancerres.aacrjournals.org on September 29, 2021. © 2018 American Association for Cancer Research. Author Manuscript Published OnlineFirst on April 4, 2018; DOI: 10.1158/1078-0432.CCR-17-1898 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. 50 Disclosure of Potential Conflicts of Interest: A.Villanueva and A.Vidal are founders and 51 shareholders of Xenopat S.L (Barcelona, Spain). No potential conflicts of interest were disclosed by 52 the other authors. 53 Word count: 5.339; Number of figures and tables: 5 54 TRASLATIONAL RELEVANCE 55 56 Cisplatin-based cytotoxic chemotherapy is the mainstay of the treatment of several 57 types of neoplasias being the acquired resistance a major clinical limitation for patient’s 58 survival. Orthoxenografts are the most advanced ex vivo platforms to investigate the 59 efficiency of drugs in a personalized manner but in this study we also demonstrated that 60 are valuable tools to identify prognosis markers and novel re-sensitizing therapeutic 61 approaches for the treatment of cisplatin refractory tumors. As proof-of-principle, in this 62 study we validate our approach demonstrating that presence of the 9q32-q33.1 gain is 63 associated with poor risk defined by shorter overall survival (OS) and that genetic or 64 pharmacological inhibition of glucosylceramide synthase (GCS) activity is efficient to 65 re-sensitize testicular and epithelial ovarian tumors refractory to cisplatin. 66 67 68 69 70 71 72 73 74 75 76 77 2 Downloaded from clincancerres.aacrjournals.org on September 29, 2021. © 2018 American Association for Cancer Research. Author Manuscript Published OnlineFirst on April 4, 2018; DOI: 10.1158/1078-0432.CCR-17-1898 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. 78 79 80 ABSTRACT 81 Purpose: To investigate the genetic basis of cisplatin resistance since efficacy of 82 cisplatin-based chemotherapy in the treatment of distinct malignancies is often 83 hampered by intrinsic or acquired drug resistance of tumor cells. 84 Experimental design: We produced 14 orthoxenograft transplanting human 85 nonseminomatous (NSE) testicular germ cell tumors (TGCTs) to mice, keeping the 86 primary tumor features in terms of genotype, phenotype and sensitivity to cisplatin. 87 Chromosomal and genetic alterations were evaluated in matched cisplatin-sensitive and 88 their counterpart orthoxenografts that developed resistance to cisplatin in nude mice. 89 Results: Comparative genomic hybridization analyses of four matched orthoxenografts 90 identified recurrent chromosomal rearrangements across cisplatin-resistant tumors in 91 three of them, showing gains at 9q32-q33.1 region. We found a clinical correlation 92 between the presence of 9q32-q33.1 gains in cisplatin refractory patients and poorer 93 overall survival in metastatic germ cell tumors. We studied the expression profile of the 94 sixty genes located at that genomic region. POLE3 and AKNA were the only two genes 95 deregulated in resistant tumors harboring the 9q32-q33.1 gain. Moreover, other four 96 genes (GCS, ZNF883, CTR1 and FLJ31713) were deregulated in all five resistant 97 tumors independently of the 9q32-q33.1 amplification. RT-PCRs in tumors and 98 functional analyses in C. elegans indicate that the influence of 9q32-q33.1 genes in 99 cisplatin resistance can be driven by either up- or down-regulation. We focused on 100 glucosylceramide synthase (GCS) to demonstrate that the GCS inhibitor DL-threo- 101 PDMP re-sensitizes cisplatin-resistant germline-derived orthoxenografts to cisplatin. 3 Downloaded from clincancerres.aacrjournals.org on September 29, 2021. © 2018 American Association for Cancer Research. Author Manuscript Published OnlineFirst on April 4, 2018; DOI: 10.1158/1078-0432.CCR-17-1898 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. 102 Conclusions: Orthoxenografts can be used preclinically not only to test the efficiency 103 of drugs but also to identify prognosis markers and gene alterations acting as drivers of 104 the acquired cisplatin resistance. 105 INTRODUCTION 106 Testicular germ cell tumors (TGCTs) of adolescent and young adults are the most 107 common malignancy in young men (1–3). They can be classified as seminomas (SEs) 108 (originated in epithelium of the seminiferous tubules), which represent around 40% of 109 cases, and nonseminomas (NSEs)(60%). Seminomas are radio- and chemo-sensitive 110 tumors highly curable at all stages. With the exception of teratomas, NSEs are also 111 highly sensitive to cisplatin-based chemotherapy and, when combined with surgery, 112 patients achieve high cure rates (4). In contrast with most advanced solid tumors, 113 approximately 80-90% of metastatic TGCTs will achieve complete cure after standard 114 doses of cisplatin (CDDP) chemotherapy (4) . Nevertheless, 10-15% of patients die due 115 to cisplatin refractoriness and the absence of alternative effective re-sensitizing 116 therapies (5–7). Such high success in treating advanced testicular cancer has limited the 117 number of studies addressing the treatment failure in refractory patients (8, 9). 118 In TGCTs, cisplatin resistance has been attributed to diverse cellular mechanisms (10– 119 12), although the molecular details underlying treatment failure in refractory patients 120 remains obscure (13–17). Patient derived orthotopic xenografts, named PDOX or 121 orthoxenografts, are relevant preclinical animal models that phenocopy human tumor 122 properties (18,19). We have previously used TGCT orthoxenografts to explore
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