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

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

doi:10.3389/fonc.2021.648097

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

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

Authors

Alex Q Lee¹, Masami Ijiri¹, Ryan Rodriguez², Regina Gandour-Edwards³, Joyce Lee⁴, Clifford G Tepper^{4

5}, Yueju Li⁶, Laurel Beckett⁶, Kit Lam⁴, Neal Goodwin², Noriko Satake¹

Affiliations

¹ Department of Pediatrics, UC Davis School of Medicine, Sacramento, CA, United States.
² The Jackson Laboratory, Sacramento, CA, United States.
³ Department of Pathology & Laboratory Medicine, UC Davis School of Medicine, Sacramento, CA, United States.
⁴ Department of Biochemistry and Molecular Medicine, UC Davis School of Medicine, Sacramento, CA, United States.
⁵ Genomics Shared Resource, UC Davis Comprehensive Cancer Center, Sacramento, CA, United States.
⁶ Department of Public Health Sciences, UC Davis, Davis, CA, United States.

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^scid Il2rg^tm1Wjl/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.

Keywords: metastatic pleural effusion; multikinase inhibitor; patient-derived xenograft model; renal medullary carcinoma; sunitinib.