A multiplex preclinical model for adenoid cystic carcinoma of the salivary gland identifies regorafenib as a potential therapeutic drug

Xuefeng Liu,Devan J Wilkins,Eric Glasgow,Thomas Ried,Danny Wangsa,Praathibha Sripadhan,Darawalee Wangsa,Michael J Wick,Sujata Choudhury,Chamille J Lescott,Christopher Moskaluk,Chen Chen,Seema Agarwal,Richard Schlegel

doi:10.1038/s41598-017-11764-2

Abstract

Adenoid cystic carcinomas (ACC) are rare salivary gland cancers with a high incidence of metastases. In order to study this tumor type, a reliable model system exhibiting the molecular features of this tumor is critical, but none exists, thereby inhibiting in-vitro studies and the analysis of metastatic behavior. To address this deficiency, we have coupled an efficient method to establish tumor cell cultures, conditional reprogramming (CR), with a rapid, reproducible and robust in-vivo zebrafish model. We have established cell cultures from two individual ACC PDX tumors that maintain the characteristic MYB translocation. Additional mutations found in one ACC culture also seen in the PDX tumor. Finally, the CR/zebrafish model mirrors the PDX mouse model and identifies regorafenib as a potential therapeutic drug to treat this cancer type that mimic the drug sensitivity profile in PDX model, further confirming the unique advantages of multiplex system.

Highlights

Adenoid cystic carcinomas (ACC) are rare salivary gland cancers with a high incidence of metastases
We have demonstrated that conditional reprogramming can be successfully used to establish well-authenticated cell cultures for ACCs that maintain the key molecular and cellular features of the tumor of origin
Drug sensitivity assays indicate that conditional reprogramming (CR) cells show similar drug sensitivity both in in-vitro and in-vivo assays and both of these assays correlate with the mouse patient-derived mouse xenografts (PDX) model

Summary

Introduction

Adenoid cystic carcinomas (ACC) are rare salivary gland cancers with a high incidence of metastases. In order to study this tumor type, a reliable model system exhibiting the molecular features of this tumor is critical, but none exists, thereby inhibiting in-vitro studies and the analysis of metastatic behavior To address this deficiency, we have coupled an efficient method to establish tumor cell cultures, conditional reprogramming (CR), with a rapid, reproducible and robust in-vivo zebrafish model. Patient-derived mouse xenografts (PDX) have been successfully established from ACC primary tumors. These PDX tumors have been shown to maintain the histology and gene expression profile of the primary tumor, making them a valid model system for drug discovery[4, 5]. These models provide the foundation for basic and translational studies, including the definition of the drivers of malignancy in this aggressive tumor

Methods

Results

Conclusion