Elst Laura, Van Rompuy Anne-Sophie, Roussel Eduard, Spans Lien, Vanden Bempt Isabelle, Necchi Andrea, Ross Jeffrey, Jacob Joseph M, Baietti Maria-Francesca, Leucci Eleonora, Albersen Maarten
Laboratory of Experimental Urology, Department of Development and Regeneration, KU Leuven, Leuven, Belgium; Department of Urology, University Hospitals Leuven, Leuven, Belgium.
Department of Pathology, University Hospitals Leuven, Leuven, Belgium.
Eur Urol Focus. 2022 Nov;8(6):1787-1794. doi: 10.1016/j.euf.2022.04.012. Epub 2022 May 7.
Systemic treatments for penile squamous cell carcinoma (pSCC) are toxic and inefficient. Patient-based preclinical models are essential to study novel treatments.
To establish a library of patient-derived tumor xenograft (PDX) models of human papillomavirus-positive (HPV) and -negative (HPV) pSCC and characterize these at the genomic and histological levels.
DESIGN, SETTING, AND PARTICIPANTS: Eighteen tumor samples from 14 patients with recurrent or metastatic pSCC were implanted in nude mice. A biobank of PDX tumors was established after passaging of patient samples (F0) for three generations (F1, F2, F3) and was characterized using histopathology and targeted next-generation sequencing (tNGS). Single-nucleotide polymorphism fingerprinting was used to confirm PDX genealogy.
The engraftment rate, overall growth rate, and pSCC histomorphology were checked for each PDX generation. Staining for p40 (a pSCC marker) and p16 (a surrogate for HPV infection) was performed for F0 samples. The mutational profile according to a validated panel of 96 cancer genes was determined for F0 and F3 samples and compared to a larger tNGS database.
Including a previously established pilot model, 11 out of 18 tumor samples (61%) successfully engrafted in F1. The mean time from implantation in F1 to completion of F3 was 36 wk (standard deviation 18). Histological fidelity was demonstrated across generations. The patient mutational profiles were preserved in F3 and were representative of 277 pSCC samples in the Foundation Medicine database. The rapid progression of pSCC in patients from our selected high-risk cohort impeded the use of PDXs as avatars.
We successfully established the first library of 11 PDX models of HPV and HPV pSCC. Our PDX models showed high engraftment rates and histological and genomic fidelity to the tumor tissue of origin. These models may help in paving the way towards the development of novel treatments.
We established 11 animal models based on tumor tissue from patients with penile cancer. These models could play a vital role in selection of novel treatments according to genetic mutations. In the future, therapies with confirmed preclinical effects may have a profound impact on the development of personalized treatments in penile cancer.
阴茎鳞状细胞癌（pSCC）的全身治疗具有毒性且效率低下。基于患者的临床前模型对于研究新型治疗方法至关重要。
建立人乳头瘤病毒阳性（HPV）和阴性（HPV）pSCC的患者来源肿瘤异种移植（PDX）模型库，并在基因组和组织学水平上对其进行表征。
设计、设置和参与者：将14例复发性或转移性pSCC患者的18个肿瘤样本植入裸鼠体内。在患者样本（F0）传代三代（F1、F2、F3）后建立PDX肿瘤生物样本库，并使用组织病理学和靶向新一代测序（tNGS）进行表征。单核苷酸多态性指纹图谱用于确认PDX谱系。
检查每个PDX代的植入率、总体生长率和pSCC组织形态学。对F0样本进行p40（一种pSCC标志物）和p16（HPV感染替代物）染色。确定F0和F3样本根据96个癌症基因的验证面板的突变谱，并与更大的tNGS数据库进行比较。
包括先前建立的一个试点模型，18个肿瘤样本中有11个（61%）在F1中成功植入。从F1植入到F3完成的平均时间为36周（标准差18）。各代均显示出组织学保真度。患者的突变谱在F3中得以保留，并且代表了Foundation Medicine数据库中的277个pSCC样本。我们所选高危队列患者中pSCC的快速进展阻碍了将PDX用作替身。
我们成功建立了首个包含11个HPV和HPV pSCC的PDX模型库。我们的PDX模型显示出高植入率以及对原发肿瘤组织的组织学和基因组保真度。这些模型可能有助于为新型治疗方法的开发铺平道路。
我们基于阴茎癌患者的肿瘤组织建立了11个动物模型。这些模型在根据基因突变选择新型治疗方法方面可能发挥至关重要的作用。未来，具有已确认临床前效果的疗法可能会对阴茎癌个性化治疗的发展产生深远影响。
