Abstract
Nasopharyngeal carcinoma (NPC) is an Epstein Barr virus (EBV)-related malignancy in which the tumor microenvironment plays a pivotal role in tumor progression. Here, we developed two patient-derived xenograft (PDX) mouse lines from engrafted NPC metastatic tumors. Positive staining for EBV-encoded small RNAs confirmed that these tumors harbored EBV, and gene expression profile analyses further showed that the PDX was highly similar to the primary parent tumor. In vivo drug screening using the PDX system demonstrated that gemcitabine had the best antitumor effect among the tested drugs. The donor of this PDX also showed excellent responsiveness to gemcitabine treatment. The combination of gemcitabine and valproic acid exerted synergistic antitumor effects. Further addition of ganciclovir to this two-drug combination regimen enhanced cytolytic viral activation, yielding the best antitumor response among tested regimens. Treatment with this three-drug combination regimen decreased plasma EBV-DNA load, tumor viral concentration, and the number of viable tumor cells to a greater extent than the two-drug gemcitabine and valproic acid combination. These results highlight the value of PDX models in the development of EBV-targeted strategies to treat NPC.
Highlights
Nasopharyngeal carcinoma (NPC) is highly prevalent in Southern Chinese populations and has a predilection to affect young adult males [1]
Exploiting the fact that engrafting rate is higher for metastatic tumors than primary site tumors, we established two mouse xenograft lines from NPC metastatic tumors: NPC01, obtained from a paraspinal soft tissue tumor at initial diagnosis of NPC with bone and soft tissue metastasis, and NPC02, obtained from a neck lymph node biopsy after three lines of chemotherapy
NPC is an Epstein Barr virus (EBV)-related cancer in which the tumor microenvironment has a crucial role in tumor progression
Summary
Nasopharyngeal carcinoma (NPC) is highly prevalent in Southern Chinese populations and has a predilection to affect young adult males [1]. In this endemic region, non-keratinizing and undifferentiated carcinoma constitutes up to 99% of all cases, and these tumors are closely related to infection with Epstein Barr virus (EBV) [2, 3]. These models exhibit a stable biological profile when passaged in mice (especially during early passages) in terms of global gene-expression patterns, mutational status, metastatic potential, drug responsiveness, and tumor architecture [8]. Primary tumor xenografts have been shown to be valuable in a tailored personalized medicine setting for drug-sensitivity screening in cases where standard treatment has failed; they could help to identify key pathway components suitable for targeted drug development [14]
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