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Original Article Establishment of Patient-Derived Xenograft Models Of Am J Cancer Res 2021;11(3):773-792 www.ajcr.us /ISSN:2156-6976/ajcr0123386 Original Article Establishment of patient-derived xenograft models of adenoid cystic carcinoma to assess pre-clinical efficacy of combination therapy of a PI3K inhibitor and retinoic acid Bao Sun1,2,3*, Yu Wang1,2,3*, Jingjing Sun1,2,3, Chunye Zhang1,2,3, Ronghui Xia1,2,3, Shengming Xu2,3,4, Shuyang Sun2,3,4, Jiang Li1,2,3 1Department of Oral Pathology, Shanghai Ninth People’s Hospital, College of Stomatology, Shanghai Jiao Tong University School of Medicine, Shanghai 200011, P. R. China; 2National Clinical Research Center for Oral Diseases, Shanghai 200011, P. R. China; 3Shanghai Key Laboratory of Stomatology & Shanghai Research Institute of Stomatology, Shanghai 200011, P. R. China; 4Department of Oral and Maxillofacial-Head & Neck Oncology, Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200011, P. R. China. *Equal contributors. Received September 29, 2020; Accepted December 30, 2020; Epub March 1, 2021; Published March 15, 2021 Abstract: Due to the difficulties and long periods of establishment, preclinical animal models of adenoid cystic carcinoma (ACC) are scarce but imperative. The researches involving molecular features and therapeutic targets of ACC require an integrated group of preclinical animal models which can credibly retain the heterogeneity of this tumor. Currently chemotherapies and targeting therapies have modest efficacy in ACC and the overall response rate is rather low. Therefore, novel therapeutic regimen of ACC is urgently needed and remains a major clinical challenge. We transplanted a group of tumor samples from human salivary ACC into immunodeficient mice to establish patient- derived xenografts (PDXs). Patient tumors and their matched PDXs were conducted histological analyses, whole- exome sequencing (WES) and RNA-seq respectively. 13 PDXs were successfully established from 34 ACC, involved in 3 histological types, including cribriform, tubular, and solid. These ACC PDXs generally reflected the histopatho- logical and molecular features of their corresponding original tumors. MYB/MYBL1-NFIB fusion (53.85%) and high- frequency mutation genes, such as KDM6A, KMT2C, KMT2D, NOTCH1, NOTCH2, SMARCA4 and PIK3CA were mainly conserved in PDXs. Guided by the genetic alterations, the efficiencies of retinoic acid (RA) and a PI3K inhibitor were evaluated in ACC PDX models harboring both MYB fusion and PIK3CA amplification/mutation. Combination treat- ment of the PI3K inhibitor and RA demonstrated remarkable inhibition of tumors in PDXs harboring both PIK3CA mutation/amplification and MYB-NFIB fusion gene in vivo and in vitro. In this study, we displayed the morphologi- cally and genetic featured PDXs which recapitulated the heterogeneity of original ACC tumors, indicating that the models could be used as a platform for drug screening for therapy response. The feasibility of combination treat- ment approaches for dual targets were confirmed, providing new regimens for personalized therapies in ACC. Keywords: Adenoid cystic carcinoma, patient-derived xenograft, WES, targeting therapy, PI3K inhibitor, retinoic acid Introduction ACC consists of typical glandular epithelial and myoepithelial cells, which arrange in cribriform, Adenoid cystic carcinoma (ACC) is among the tubular and solid patterns with abundant hya- most prevalent salivary malignancies, and also line extracellular secretion [2]. High-grade ACC, occurred in breast, lung and lacrimal gland, etc. with substantial solid components in the tumor, Although ACC exhibits indolent growth, it has a is associated with a more advanced stage and confirmed propensity for aggressive perineural more prefer to distant metastases [3]. Current invasion and high rates of distant metastasis, treatments are still mainly surgery and adjuvant which ultimately result in low survival rates radiation, and no systemic chemotherapy has and poor prognosis [1]. In histomorphology, been proven to be fully effective [4]. The mecha- Establishment of PDXs of ACC and pre-clinical efficacy of combination therapy nisms involved in ACC are still poorly under- peutic regimen is required to improve long-term stood. One important genetic alteration in ACC outcomes for ACC patients currently. is the recurrent t(6;9) (q22-23; p23-24) translo- cation, which is considered as a hallmark in the The conventional cancer cell lines and animal pathogenesis of this disease and results in a models fail to accurately recapitulate intratu- fusion gene named MYB-NFIB [5, 6]. This fusion mor heterogeneity of ACC. ACC PDXs faithfully gene has been reported in over 50% of ACCs retain the morphological and genetic character- and results in overexpression of MYB protein, istics of the original tumors and have promoted suggesting that MYB may be a potential thera- the progress of the preclinical and translational peutic target for ACC [7]. Previous evidence research [19]. PDX models are established by indicated that retinoic acid restrained MYB subcutaneous implantation of small pieces expression, possibly by interrupting MYB-driven of patient tumors into immunodeficient mice, transcriptional regulation [8]. At present, clini- which are propagated to obtain cohorts of ani- cal trials using all-trans retinoic acid has being mals bearing tumors from patients. In addition, recruited for patients with confirmed advanced, tumor biological markers can be identified and recurrent/metastatic ACC (Clinical Trials.gov: then preclinical trials can be performed though NCT04433169). PDXs to evaluate the responses to targeted drugs [20]. Indeed, several studies in PDX mod- On account of the complexity of this disease els of ACC generated important preclinical process and the unclear etiology, no standard information that led to the further execution of treatment regimen has been designed for ACC, clinical trials. Felipe Nör et al demonstrated which still consists of surgery and radiotherapy that a small molecule (MI-773) interrupted [9]. There is no recommended specific chemo- MDM2-p53 interaction and sensitized to cispla- therapeutic regimen and conventional chemo- tin in low-passage primary human ACC models therapeutic regimens, such as cisplatin and [21]. Knowledge about the underlying genomic doxorubicin, remain being used in clinical treat- landscape of ACC is needed to understand, ments [10]. Consideration of the modest effi- leading to the development of effective thera- cacy of current chemotherapies in ACC, thera- pies in future. pies targeting various molecular have applied to clinical trials in an aim to improve the long- Here, we provided genomic profiles of a panel term prognosis of patients. NOTCH1 mutation of salivary ACC and established a group of has been defined as a distinct group character- PDX models. Through whole-exome sequencing ized by solid histology, distant metastasis, and (WES), bioinformatic analysis and histopatho- poor prognosis [11]. Recently, clinical trials tar- logical verification, we found that the PDXs re- geting NOTCH signaling (confirmed ACC with capitulated the genetic stability of the matched NOTCH1/2/3/4 activating mutation) in a geno- primary tumors. Based on the previous results, type-defined ACC subgroup have being per- a PI3K inhibitor was selected for combination formed in a phase II clinical trial, which is still efficacy evaluation with RA in PDXs and PDX- recruiting (Clinical Trials.gov: NCT03691207). derived cells with PIK3CA amplification/muta- tion and MYB. In addition, combination of the Overexpression of c-KIT has been reported in PI3K inhibitor with conventional therapies were majority of ACCs, but inhibitors of c-KIT (e.g., further assessed. dasatinib) are shown to be ineffective in a phase II clinical trial [12]. Drugs interfering epi- Materials and methods dermal growth factor receptor (EGFR), including cetuximab, gefitinib or lapatinib, did not ob- Patient tumor sample preparations tain objective responses, but some patients attained prolonged stabilization [13-15]. More- Tumor collection and related studies were per- over, other clinical trials involving targeted ther- mitted by the Institutional Review Board and apies for FGFR (fibroblast growth factor recep- the Ethics Committee of Shanghai Ninth Peo- tor, FGFR), HER2 and VEGFR (vascular endothe- ple’s Hospital, Shanghai Jiao Tong University lial growth factor receptor, VEGFR) showed par- School of Medicine. After patients’ informed tial response [16-18]. Single agent, either in permission, fresh specimens were acquired clinical trials or basic research, has not yielded from patients undergoing surgical resection active results yet. Effective combined thera- without radiotherapy or chemotherapy. All ACC 774 Am J Cancer Res 2021;11(3):773-792 Establishment of PDXs of ACC and pre-clinical efficacy of combination therapy cases were diagnosed by at least two different ies were constructed using the Illumina TruSeq pathologists. for mRNA. The libraries were sequenced at 2×100 paired-end at a mean coverage of 100- Establishment of xenografts 200× depth in the annotated transcriptome. Fresh tumors were obtained from ACC patients Clustering and sequencing: The sample cluster- and immediately immersed in cold DMEM with ing was conducted through a cBot Cluster Ge- 1% penicillin and streptomycin. After briefly neration System (Hiseq PE 150 Cluster Kit, processing, tumor tissues from patients were Illumina, CA, USA) according to the manufac- minced into small fragments (approximately turer’s recommendations.
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