Zacharias Niki M, Segarra Luis, Akagi Keiko, Fowlkes Natalie Wall, Chen Huiqin, Alaniz Angelita, de la Cerda Carolyn, Pesquera Pedro, Xi Yuanxin, Wang Jing, Chahoud Jad, Lu Xin, Rao Priya, Martinez-Ferrer Magaly, Pettaway Curtis A
Department of Urology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
MD Anderson UTHealth Graduate School, Houston, TX 77030, USA.
Cancers (Basel). 2024 Mar 6;16(5):1066. doi: 10.3390/cancers16051066.
Metastatic penile squamous cell carcinoma (PSCC) has only a 50% response rate to first-line combination chemotherapies and there are currently no targeted-therapy approaches. Therefore, we have an urgent need in advanced-PSCC treatment to find novel therapies. Approximately half of all PSCC cases are positive for high-risk human papillomavirus (HR-HPV). Our objective was to generate HPV-positive (HPV+) and HPV-negative (HPV-) patient-derived xenograft (PDX) models and to determine the biological differences between HPV+ and HPV- disease. We generated four HPV+ and three HPV- PSCC PDX animal models by directly implanting resected patient tumor tissue into immunocompromised mice. PDX tumor tissue was found to be similar to patient tumor tissue (donor tissue) by histology and short tandem repeat fingerprinting. DNA mutations were mostly preserved in PDX tissues and similar APOBEC (apolipoprotein B mRNA editing catalytic polypeptide) mutational fractions in donor tissue and PDX tissues were noted. A higher APOBEC mutational fraction was found in HPV+ versus HPV- PDX tissues ( = 0.044), and significant transcriptomic and proteomic expression differences based on HPV status included p16 (CDKN2A), RRM2, and CDC25C. These models will allow for the direct testing of targeted therapies in PSCC and determine their response in correlation to HPV status.
转移性阴茎鳞状细胞癌（PSCC）对一线联合化疗的缓解率仅为50%，目前尚无靶向治疗方法。因此，我们迫切需要在晚期PSCC治疗中寻找新的治疗方法。所有PSCC病例中约有一半高危人乳头瘤病毒（HR-HPV）呈阳性。我们的目标是建立HPV阳性（HPV+）和HPV阴性（HPV-）患者来源的异种移植（PDX）模型，并确定HPV+和HPV-疾病之间的生物学差异。通过将切除的患者肿瘤组织直接植入免疫缺陷小鼠体内，我们建立了4个HPV+和3个HPV-的PSCC PDX动物模型。通过组织学和短串联重复指纹图谱发现，PDX肿瘤组织与患者肿瘤组织（供体组织）相似。DNA突变大多保留在PDX组织中，并且在供体组织和PDX组织中观察到相似的载脂蛋白B mRNA编辑催化多肽（APOBEC）突变率。在HPV+与HPV-的PDX组织中发现了更高的APOBEC突变率（ = 0.044），基于HPV状态的显著转录组和蛋白质组表达差异包括p16（CDKN2A）、核糖核苷酸还原酶M2（RRM2）和细胞周期蛋白依赖性激酶25C（CDC25C）。这些模型将允许直接测试PSCC中的靶向治疗，并确定它们与HPV状态相关的反应。
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