PO.TB04.04 · 肿瘤生物学

HPV+ and HPV- head and neck cancer patient-derived models in the NCI Patient-Derived Models Repository

编号 6067 展板 13 🕑 4/21 02:00–05:00 📍 Section 26 主讲 Yvonne Evrard, PhD

分会场 In Vivo Models 2: Genetically Engineered Mouse Models, PDXs, Syngeneic Models

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作者与单位 Authors & Affiliations

Yvonne A. Evrard¹, Ting-Chia Chang², Jasmine B'Lanton¹, Gareth Bliss¹, Alice Chen³, Li Chen², Kevin Cooper¹, Kristin Cox¹, Natalie Czarra¹, Isabella Czernia¹, Biswajit Das², Kelly Dougherty¹, Aarin Dreyer¹, Lindsay Dutko², Katie Frey¹, Marion Gibson¹, Tara Grinnage-Pulley⁴, Shahanawaz Jiwani², Poorva Juneja², Keegan Kalmbach¹, Tamikia Lamb¹, Eva Loewenstein¹, Candace Mallow¹, Chelsea McGlynn¹, Justine Mills¹, Michael Mullendore¹, Matthew Murphy¹, Sandra Navas-Reyes¹, Michelle Norris¹, Jessica Park², Kaci Paulus², Kevin Plater¹, Tia Shearer¹, Jessica Steed¹, Luke Stockwin¹, Howard Stotler¹, Ruth Thornton², Cindy R. Timme¹, Shannon Uzelac¹, Dianne L. Newton¹, Chris A. Karlovich², Melinda G. Hollingshead⁴, James H. Doroshow³

¹Frederick National Laboratory for Cancer Research, Frederick, MD,²Molecular Characterization Laboratory, Frederick National Laboratory for Cancer Research, Frederick, MD,³Division of Cancer Treatment and Diagnosis, National Cancer Institute, Bethesda, MD,⁴Biological Testing Branch, Developmental Therapeutics Program, National Cancer Institute-Frederick, Frederick, MD

摘要 Abstract

Head and neck (HN) cancers are a rare set of cancers defined by their anatomical point of origin including mouth, sinus, throat, or nose. Human papilloma virus (HPV) infection plays a pathogenic role in HN cancers resulting in distinct clinical and molecular characteristics from those that are HPV-. The National Cancer Institute's Patient-Derived Models Repository (NCI PDMR; https://pdmr.cancer.gov) has developed a national repository of patient-derived models (PDMs) comprised of patient-derived xenografts (PDXs), organoids (PDOrg), tumor cell cultures (PDCs) and cancer associated fibroblasts (CAFs). These models are clinically annotated with molecular information available in a public database for the extramural community. To date, 361 patient HN tumor specimens have been received from 351 unique patients across a range of histologies including lip/oral, pharyngeal, laryngeal, salivary and sinonasal with an overall PDX take rate of 48% (322 assessable specimens). The NCI PDMR currently has 200 public HN PDX, PDOrg, and PDC models from 124 unique patients. Thirty-three models (PDX, PDOrg, PDC) from 20 unique patients are positive for HPV16 or 18 (one double positive) as detected by PCR and one sinonasal PDOrg model is positive for HPV33 identified in NextGenSeq data. As has been reported in the clinical literature, TP53 and CDKN2A mutations are found predominantly in PDX models that are HPV- (84% and 65%, respectively) but not HPV+ (0%; 0%) and PIK3CA is more commonly mutated in HPV+ models (47% vs 25%). No significant difference in loss of heterozygosity is observed in the models. However, significant differences in chromosome arm copy number changes (copy gains in 7p, 11p and 12p and copy losses in 3p, 9p and 18q [P-value<0.05; Wilcoxon Rank-Sum test]) are observed in HPV- compared to HPV+ models. Gene set enrichment analysis (GSEA) suggest the E2F_TARGETS, G2M_CHECKPOINT, and DNA_REPAIR gene sets are significantly up-regulated in HPV+ while the APOPTOSIS gene set is significantly down-regulated using MSigDB Hallmark dataset (P-value<0.05). In all analyses, differences are consistent whether examining in vivo PDX models or in vitro PDC/PDOrg models indicating the fidelity of the models. These preclinical models recapitulate the molecular differences reported in HPV+ versus HPV- clinical cases providing an important tool for the development of novel therapeutics for HN cancers. Funded by NCI Contract No. HHSN261200800001E

利益披露 Disclosure

Y. A. Evrard, None.. T. Chang, None.. J. B'Lanton, None.. G. Bliss, None.. A. Chen, None.. L. Chen, None.. K. Cooper, None.. K. Cox, None.. N. Czarra, None.. I. Czernia, None.. B. Das, None.. K. Dougherty, None.. A. Dreyer, None.. L. Dutko, None.. K. Frey, None.. M. Gibson, None.. T. Grinnage-Pulley, None.. S. Jiwani, None.. P. Juneja, None.. K. Kalmbach, None.. T. Lamb, None.. E. Loewenstein, None.. C. Mallow, None.. C. McGlynn, None.. J. Mills, None.. M. Mullendore, None.. M. Murphy, None.. S. Navas-Reyes, None.. M. Norris, None.. J. Park, None.. K. Paulus, None.. K. Plater, None.. T. Shearer, None.. J. Steed, None.. L. Stockwin, None.. H. Stotler, None.. R. Thornton, None.. C. R. Timme, None.. S. Uzelac, None.. D. L. Newton, None.. C. A. Karlovich, None.. M. G. Hollingshead, None.. J. H. Doroshow, None.

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