Establishment and Use of Patient-Derived Xenograft Models for Drug Testing in Head and Neck Squamous Cell Carcinoma.
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ABSTRACT:
SUBMITTER: Karamboulas C
PROVIDER: S-EPMC7580210 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Tumour hypoxia is a marker of poor prognosis and failure of chemoradiotherapy in head and neck squamous cell carcinoma (HNSCC), providing a strategy for therapeutic intervention in this setting. To evaluate the utility of the hypoxia-activated prodrug evofosfamide (TH-302) in HNSCC, we established ten early passage patient-derived xenograft (PDX) models of HNSCC that were characterised by their histopathology, hypoxia status, gene expression, and sensitivity to evofosfamide. All PDX models closely resembled the histology of the patient tumours they were derived from. Pimonidazole-positive tumour hypoxic fractions ranged from 1.7-7.9% in line with reported HNSCC clinical values, while mRNA expression of the Toustrup hypoxia gene signature showed close correlations between PDX and matched patient tumours, together suggesting the PDX models may accurately model clinical tumour hypoxia. Evofosfamide as a single agent (50 mg/kg IP, qd × 5 for three weeks) demonstrated antitumour efficacy that was variable across the PDX models, ranging from complete regressions in one p16-positive PDX model to lack of significant activity in the three most resistant models. Despite all PDX models showing evidence of tumour hypoxia, and hypoxia being essential for activation of evofosfamide, the antitumour activity of evofosfamide only weakly correlated with tumour hypoxia status determined by pimonidazole immunohistochemistry. Other candidate evofosfamide sensitivity genes-MKI67, POR, and SLFN11-did not strongly influence evofosfamide sensitivity in univariate analyses, although a weak significant relationship with MKI67 was observed, while SLFN11 expression was lost in PDX tumours. Overall, these data confirm that evofosfamide has antitumour activity in clinically-relevant PDX tumour models of HNSCC and support further clinical evaluation of this drug in HNSCC patients. Further research is required to identify those factors that, alongside hypoxia, can influence sensitivity to evofosfamide and could act as predictive biomarkers to support its use in precision medicine therapy of HNSCC.
| S-EPMC6678517 | biostudies-literature
Project description:BACKGROUND:We investigated whether head and neck squamous cell carcinoma (HNSCC) patient-derived xenografts (PDXs) reaffirm patient responses to anti-cancer therapeutics. METHODS:Tumors from HNSCC patients were transplanted into immunodeficient mice and propagated via subsequent implantation. We evaluated established PDXs by histology, genomic profiling, and in vivo anti-cancer efficacy testing to confirm them as the authentic in vivo platform. RESULTS:From 62 HNSCCs, 15 (24%) PDXs were established. The primary cancer types were tongue (8), oropharynx (3), hypopharynx (1), ethmoid sinus cancer (1), supraglottic cancer (1), and parotid gland (1); six PDXs (40%) were established from biopsy specimens from advanced HNSCC. PDXs mostly retained donor characteristics and remained stable across passages. PIK3CA (H1047R), HRAS (G12D), and TP53 mutations (H193R, I195T, R248W, R273H, E298X) and EGFR, CCND1, MYC, and PIK3CA amplifications were identified. Using the acquisition method, biopsy showed a significantly higher engraftment rate when compared with that of surgical resection (100% [6/6] vs. 16.1% [9/56], P?<?0.001). Specimens obtained from metastatic sites showed a significantly higher engraftment rate than did those from primary sites (100% [9/9] vs. 11.3% [6/53], P?<?0.001). Three PDX models from HPV-positive tumors were established, as compared to 12 from HPV-negative (15.8% [3/19] and 27.9% [12/43] respectively, P?=?0.311), suggesting that HPV positivity tends to show a low engraftment rate. Drug responses in PDX recapitulated the clinical responses of the matching patients with pan-HER inhibitors and pan-PI3K inhibitor. CONCLUSIONS:Genetically and clinically annotated HNSCC PDXs could be useful preclinical tools for evaluating biomarkers, therapeutic targets, and new drug discovery.
| S-EPMC7160896 | biostudies-literature
Project description:Mucinous ovarian carcinoma (mEOC) represents a rare subtype of epithelial ovarian cancer, accounting for 3-4% of all ovarian carcinomas. The rarity of this tumor type renders both the preclinical and clinical research compelling. Very few preclinical in vitro and in vivo models exist. We here report the molecular, metabolic and pharmacological characterization of two patient derived xenografts (PDXs) from mEOC, recently obtained in our laboratory. These PDXs maintain the histological and molecular characteristics of the patient's tumors they derived from, including a wild type TP53. Gene expression analysis and metabolomics profile suggest that they differ from high grade serous/endometrioid ovarian carcinoma PDXs. The pharmacological characterization was undertaken testing the in vivo antitumor activity of both cytotoxic agents (cisplatin, paclitaxel, yondelis, oxaliplatin and 5-fluorouracile) and targeted agents (bevacizumab and lapatinib). These newly established mucinous PDXs do recapitulate mEOC and will be of value in the preclinical development of possible new therapeutic strategies for this tumor type.
| S-EPMC7061742 | biostudies-literature
Project description:Patient-derived xenografts (PDX) have a biologically stable in tumor architecture, drug responsiveness, mutational status and global gene-expression patterns. Numerous PDX models have been established to date, however their thorough characterization regarding the tumor formation and rates of tumor growth in the established models remains a challenging task. Our study aimed to provide more detailed information for establishing the PDX models successfully and effectively.We transplanted four different types of solid tumors from 108 Chinese patients, including 21 glioblastoma (GBM), 11 lung cancers (LC), 54 gastric cancers (GC) and 21 colorectal cancers (CRC), and took tumor tissues passaged for three successive generations. Here we report the rate of tumor formation, tumor-forming times, tumor growth curves and mortality of mice in PDX model. We also report H&E staining and immunohistochemistry for HLA-A, CD45, Ki67, GFAP, and CEA protein expression between patient cancer tissues and PDX models.Tumor formation rate increased significantly in subsequent tumor generations. Also, the survival rates of GC and CRC were remarkably higher than GBM and LC. As for the time required for the formation of tumors, which reflects the tumor growth rate, indicated that tumor growth rate always increased as the generation number increased. The tumor growth curves also illustrate this law. Similarly, the survival rate of PDX mice gradually improved with the increased generation number in GC and CRC. And generally, there was more proliferation (Ki67+) in the PDX models than in the patient tumors, which was in accordance with the results of tumor growth rate. The histological findings confirm similar histological architecture and degrees of differentiation between patient cancer tissues and PDX models with statistical analysis by GraphPad Prism 5.0.We established four different types of PDX models successfully, and our results add to the current understanding of the establishment of PDX models and may contribute to the extension of application of different types of PDX models.
| S-EPMC5738885 | biostudies-other
Project description:BackgroundHead and neck squamous cell carcinoma (HNSCC) is heterogeneous in etiology, phenotype and biology. Patient-derived xenografts (PDX) maintain morphology and molecular profiling of the original tumors and have become a standard "Avatar" model for human cancer research. However, restricted availability of tumor samples hindered the widespread use of PDX. Most PDX-projects include only surgical specimens because reliable engraftment from biopsies is missing. Therefore, sample collection is limited and excludes recurrent and metastatic, non-resectable cancer from preclinical models as well as future personalized medicine.MethodsThis study compares the PDX-take rate, -growth, histopathology, and molecular characteristics of endoscopic specimens with surgical specimens. HNSCC samples (n = 55) were collected ad hoc, fresh frozen and implanted into NOD.Cg-PrkdcscidIl2rgtm1Wjl/SzJ mice.ResultsEngraftment was successful in both sample types. However, engraftment rate was lower (21 vs. 52%) and growth delayed (11.2 vs. 6.7 weeks) for endoscopic biopsies. Following engraftment, growth kinetic was similar. Comparisons of primary tumors and corresponding PDX models confirmed preservation of histomorphology (HE histology) and molecular profile (Illumina Cancer Hotspot Panel) of the patients' tumors. Accompanying flow cytometry on primary tumor specimens revealed a heterogeneous tumor microenvironment among individual cases and identified M2-like macrophages as positive predictors for engraftment. Vice versa, a high PD-L1 expression (combined positive score on tumor/immune cells) predicted PDX rejection.ConclusionIncluding biopsy samples from locally advanced or metastatic lesions from patients with non-surgical treatment strategies, increases the availability of PDX for basic and translational research. This facilitates (pre-) clinical studies for individual response prediction based on immunological biomarkers.
| S-EPMC8344210 | biostudies-literature
Project description:Patient survival from head and neck squamous cell carcinoma (HNSCC), the seventh most common cause of cancer, has not markedly improved in recent years despite the approval of targeted therapies and immunotherapy agents. Precision medicine approaches that seek to individualise therapy through the use of predictive biomarkers and stratification strategies offer opportunities to improve therapeutic success in HNSCC. To enable precision medicine of HNSCC, an understanding of the microenvironment that influences tumour growth and response to therapy is required alongside research tools that recapitulate the features of human tumours. In this review, we highlight the importance of the tumour microenvironment in HNSCC, with a focus on tumour hypoxia, and discuss the fidelity of patient-derived xenograft and organoids for modelling human HNSCC and response to therapy. We describe the benefits of patient-derived models over alternative preclinical models and their limitations in clinical relevance and how these impact their utility in precision medicine in HNSCC for the discovery of new therapeutic agents, as well as predictive biomarkers to identify patients' most likely to respond to therapy.
| S-EPMC7763264 | biostudies-literature
Project description:BACKGROUND:One of the key reasons for the high failure rate of new agents and low therapeutic benefit of approved treatments is the lack of preclinical models that mirror the biology of human tumors. At present, the optimal cancer model for drug response study to date is patient-derived xenograft (PDX) models. PDX recaptures both inter- and intra-tumor heterogeneity inherent in human cancer, which represent a valuable platform for preclinical drug testing and personalized medicine applications. Building efficient drug response analysis tools is critical but far from adequate for the PDX platform. RESULTS:In this work, we first classified the emerging PDX preclinical trial designs into four patterns based on the number of tumors, arms, and animal repeats in every arm. Then we developed an R package, DRAP, which implements Drug Response Analyses on PDX platform separately for the four patterns, involving data visualization, data analysis and conclusion presentation. The data analysis module offers statistical analysis methods to assess difference of tumor volume between arms, tumor growth inhibition (TGI) rate calculation to quantify drug response, and drug response level analysis to label the drug response at animal level. In the end, we applied DRAP in two case studies through which the functions and usage of DRAP were illustrated. CONCLUSION:DRAP is the first integrated toolbox for drug response analysis and visualization tailored for PDX platform. It would greatly promote the application of PDXs in drug development and personalized cancer treatments.
| S-EPMC6350365 | biostudies-literature
Project description:Head and neck squamous cell carcinomas (HNSCC) represent a group of epithelial neoplasms that exhibit considerable heterogeneity in clinical behavior. Here, we examined the stromal and vascular heterogeneity in a panel of patient-derived xenograft (PDX) models of HNSCC and the impact on therapeutic response. Tumor sections from established tumors were stained for p16 (surrogate for human papillomavirus (HPV) infection), stromal (Masson's trichrome) and vascular (CD31) markers. All PDX models retained the HPV/p16 status of the original patient tumor. Immunohistochemical evaluation revealed the presence of multiple vessel phenotypes (tumor, stromal or mixed) in the PDX panel. Vascular phenotypes identified in the PDX models were validated in a tissue microarray of human HNSCC. Treatment with a microtubule targeted vascular disrupting agent (VDA) resulted in a heterogeneous antivascular and antitumor response in PDX models. The PDX with the tumor vessel phenotype that exhibited higher CD31+ vessel counts and leaky vasculature on magnetic resonance imaging (MRI) was sensitive to VDA treatment while the PDX with the stromal vessel phenotype was resistant to therapy. Collectively, our results demonstrate the phenotypic and functional vascular heterogeneity in HNSCC and highlight the impact of this heterogeneity on response to antivascular therapy in PDX models of HNSCC.
| S-EPMC6679003 | biostudies-literature
Project description:Gastroenteropancreatic neuroendocrine neoplasms (GEP NENs) are rare cancers consisting of neuroendocrine carcinomas (NECs) and neuroendocrine tumors (NETs), which have been increasing in incidence in recent years. Few cell lines and pre-clinical models exist for studying GEP NECs and NETs, limiting the ability to discover novel imaging and treatment modalities. To address this gap, we isolated tumor cells from cryopreserved patient GEP NECs and NETs and injected them into the flanks of immunocompromised mice to establish patient-derived xenograft (PDX) models. Two of six mice developed tumors (NEC913 and NEC1452). Over 80% of NEC913 and NEC1452 tumor cells stained positive for Ki67. NEC913 PDX tumors expressed neuroendocrine markers such as chromogranin A (CgA), synaptophysin (SYP), and somatostatin receptor-2 (SSTR2), whereas NEC1452 PDX tumors did not express SSTR2. Exome sequencing revealed loss of TP53 and RB1 in both NEC tumors. To demonstrate an application of these novel NEC PDX models for SSTR2-targeted peptide imaging, the NEC913 and NEC1452 cells were bilaterally injected into mice. Near infrared-labelled octreotide was administered and the fluorescent signal was specifically observed for the NEC913 SSTR2 positive tumors. These 2 GEP NEC PDX models serve as a valuable resource for GEP NEN therapy testing.
| S-EPMC9033026 | biostudies-literature
Project description:Therapeutic innovation for human papilloma virus-related (HPV+) head and neck squamous cell carcinomas (HNSCCs) is impaired by inadequate preclinical models and the absence of accurate biomarkers. Our study establishes the first well-characterized panel of patient-derived xenografts (PDXs) and organoids from HPV+ HNSCCs while determining fidelity of the models to the distinguishing genetic features of this cancer type. Despite low engraftment rates, whole exome sequencing showed that PDXs retain multiple distinguishing features of HPV+ HNSCC lost in existing cell lines, including PIK3CA mutations, TRAF3 deletion and the absence of EGFR amplifications. Engrafted HPV+ tumors frequently contained NOTCH1 mutations, thus providing new models for a negatively prognostic alteration in this disease. Genotype-phenotype associations in the models were then tested for prediction of tumor progression and survival in published clinical cohorts. Observation of high tumor mutational burdens (TMBs) in the faster-growing models facilitated identification of a novel association between TMB and local progression in both HPV+ and HPV- patients that was prognostic in HPV- cases. In addition, reduced E7 and p16INK4A levels found in a PDX from an outlier case with lethal outcome led to detection of similar profiles among recurrent HPV+ HNSCCs. Transcriptional data from the Cancer Genome Atlas was used to demonstrate that the lower E2F target gene expression predicted by reduced E7 levels has potential as a biomarker of disease recurrence risk. Our findings bridge a critical gap in preclinical models for HPV+ HNSCCs and simultaneously reveal novel potential applications of quantifying mutational burden and viral oncogene functions for biomarker development.
| S-EPMC7554059 | biostudies-literature