新型肾髓质癌患者转移性胸腔积液来源的异种移植模型显示了舒尼替尼的治疗效果。

Novel Patient Metastatic Pleural Effusion-Derived Xenograft Model of Renal Medullary Carcinoma Demonstrates Therapeutic Efficacy of Sunitinib.

作者信息

Lee Alex Q, Ijiri Masami, Rodriguez Ryan, Gandour-Edwards Regina, Lee Joyce, Tepper Clifford G, Li Yueju, Beckett Laurel, Lam Kit, Goodwin Neal, Satake Noriko

机构信息

Department of Pediatrics, UC Davis School of Medicine, Sacramento, CA, United States.

The Jackson Laboratory, Sacramento, CA, United States.

出版信息

Front Oncol. 2021 Mar 26;11:648097. doi: 10.3389/fonc.2021.648097. eCollection 2021.

DOI:10.3389/fonc.2021.648097

PMID:33842362

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC8032976/

Abstract

BACKGROUND

Renal medullary carcinoma (RMC) is a rare but aggressive tumor often complicated by early lung metastasis with few treatment options and very poor outcomes. There are currently no verified RMC patient-derived xenograft (PDX) mouse models established from metastatic pleural effusion (PE) available to study RMC and evaluate new therapeutic options.

METHODS

Renal tumor tissue and malignant PE cells from an RMC patient were successfully engrafted into 20 NOD.Cg-Prkdc Il2rg/SzJ (NSG) mice. We evaluated the histopathological similarity of the renal tumor and PE PDXs with the original patient renal tumor and PE, respectively. We then evaluated the molecular integrity of the renal tumor PDXs between passages, as well as the PE PDX compared to two generations of renal tumor PDXs, by microarray analysis. The therapeutic efficacy of sunitinib and temsirolimus was tested in a serially-transplanted generation of 27 PE PDX mice.

RESULTS

The pathologic characteristics of the patient renal tumor and patient PE were retained in the PDXs. Gene expression profiling revealed high concordance between the two generations of renal tumor PDXs (RMC-P0 vs. RMC-P1, r=0.865), as well as between the first generation PE PDX and each generation of the renal tumor PDX (PE-P0 vs. RMC-P0, r=0.919 and PE-P0 vs. RMC-P1, r=0.843). A low number (626) of differentially-expressed genes (DEGs) was seen between the first generation PE PDX and the first generation renal tumor PDX. In the PE-P1 xenograft, sunitinib significantly reduced tumor growth (p<0.001) and prolonged survival (p=0.004) compared to the vehicle control.

CONCLUSIONS

A metastatic PE-derived RMC PDX model was established and shown to maintain histologic features of the patient cancer. Molecular integrity of the PDX models was well maintained between renal tumor and PE PDX as well as between two successive renal tumor PDX generations. Using the PE PDX model, sunitinib demonstrated therapeutic efficacy for RMC. This model can serve as a foundation for future mechanistic and therapeutic studies for primary and metastatic RMC.

摘要

背景

肾髓质癌（RMC）是一种罕见但侵袭性强的肿瘤，常伴有早期肺转移，治疗选择有限且预后极差。目前尚无从转移性胸腔积液（PE）建立的经过验证的RMC患者来源异种移植（PDX）小鼠模型用于研究RMC和评估新的治疗方案。

方法

将一名RMC患者的肾肿瘤组织和恶性PE细胞成功植入20只NOD.Cg-Prkdc Il2rg/SzJ（NSG）小鼠体内。我们分别评估了肾肿瘤和PE PDX与原始患者肾肿瘤和PE的组织病理学相似性。然后，通过微阵列分析，我们评估了传代之间肾肿瘤PDX的分子完整性，以及与两代肾肿瘤PDX相比的PE PDX的分子完整性。在27只PE PDX小鼠的连续传代中测试了舒尼替尼和替西罗莫司的治疗效果。

结果

患者肾肿瘤和患者PE的病理特征在PDX中得以保留。基因表达谱显示两代肾肿瘤PDX之间（RMC-P0与RMC-P1，r=0.865）以及第一代PE PDX与每一代肾肿瘤PDX之间（PE-P0与RMC-P0，r=0.919以及PE-P0与RMC-P1，r=0.843）具有高度一致性。在第一代PE PDX和第一代肾肿瘤PDX之间观察到少量（626个）差异表达基因（DEG）。在PE-P1异种移植中，与载体对照相比，舒尼替尼显著降低了肿瘤生长（p<0.001）并延长了生存期（p=0.004）。