PO.TB04.04 · 肿瘤生物学

NCI患者来源模型库中的HPV+和HPV-头颈癌患者来源模型

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

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

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

查看 PDF 下载 PDF 🔒 查看 / 下载完整 PDF 需登录并开通下载套餐 · 查看套餐 / 开通 AACR 官方页面

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

中文摘要

头颈（HN）癌是一组罕见的癌症，由其解剖起源点定义，包括口腔、鼻窦、咽喉或鼻。人乳头瘤病毒（HPV）感染在HN癌中发挥致病作用，产生与HPV-者不同的临床和分子特征。美国国家癌症研究所患者来源模型库（NCI PDMR；https://pdmr.cancer.gov）已开发出一个全国性的患者来源模型（PDM）库，包括患者来源异种移植（PDX）、类器官（PDOrg）、肿瘤细胞培养物（PDC）和癌症相关成纤维细胞（CAF）。这些模型经过临床注释，其分子信息在公共数据库中供机构外群体使用。迄今为止，已从351名独特患者接收到361份HN肿瘤标本，涵盖包括唇/口腔、咽、喉、唾液腺和鼻窦在内的多种组织学类型，总体PDX成功率为48%（322份可评估标本）。NCI PDMR目前拥有来自124名独特患者的200个公开HN PDX、PDOrg和PDC模型。经PCR检测，来自20名独特患者的33个模型（PDX、PDOrg、PDC）对HPV16或18呈阳性（一个双重阳性），并且在NextGenSeq数据中鉴定出一个鼻窦PDOrg模型对HPV33呈阳性。正如临床文献所报道，TP53和CDKN2A突变主要见于HPV-的PDX模型（分别为84%和65%），而非HPV+模型（0%；0%），而PIK3CA在HPV+模型中更常发生突变（47% vs 25%）。在模型中未观察到杂合性缺失的显著差异。然而，与HPV+模型相比，HPV-模型中观察到染色体臂拷贝数变化的显著差异（7p、11p和12p的拷贝增加，以及3p、9p和18q的拷贝丢失[P值<0.05；Wilcoxon秩和检验]）。基因集富集分析（GSEA）提示，使用MSigDB Hallmark数据集，E2F_TARGETS、G2M_CHECKPOINT和DNA_REPAIR基因集在HPV+中显著上调，而APOPTOSIS基因集显著下调（P值<0.05）。在所有分析中，无论检查体内PDX模型还是体外PDC/PDOrg模型，差异均保持一致，表明模型的保真度。这些临床前模型重现了在HPV+与HPV-临床病例中报道的分子差异，为开发HN癌新型疗法提供了重要工具。由NCI合同编号HHSN261200800001E资助。

查看英文原文 English 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.

← 返回 AACR 2026 检索