Serial patient-derived orthotopic xenografting of adenoid cystic carcinomas recapitulates stable expression of phenotypic alterations and innervation

Cornett, Ashley; Athwal, Harleen K.; Hill, Emily; Murphy, Gëorge F.; Yeoh, Kenji; Moskaluk, Christopher A.; Witt, Robert L.; D’Silva, Nisha J.; Agarwal, Seema; Lombaert, Isabelle M.A.

doi:10.1016/j.ebiom.2019.02.011

Cited by 14 publications

(19 citation statements)

References 37 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…We then tried to generate PDX ACC model as Cornett et al has reported previously 25 . As shown in Figure 1, PDX ACC model have been successfully established from four of six ACC patients (YCU‐ACC‐10 could not be prepared for PDX procedure because of too small sample from the original tumor).…”

Section: Resultsmentioning

confidence: 99%

See 1 more Smart Citation

Establishment of PDX‐derived salivary adenoid cystic carcinoma cell lines using organoid culture method

Takada

Aizawa

Sano

et al. 2020

Intl Journal of Cancer

View full text Add to dashboard Cite

To generate a reliable preclinical model system exhibiting the molecular features of salivary adenoid cystic carcinoma (ACC) whose biology is still unclear due to the paucity of stable cell cultures. To develop new in vitro and in vivo models of ACC, the techniques of organoid culture and patient-derived tumor xenograft (PDX), which have attracted attention in other malignancies in recent years, were applied. Tumor specimens from surgically resected salivary ACC were proceeded for the preparation of PDX and organoid culture. The orthotopic transplantation of patient-derived or PDX-derived organoids was demonstrated into submandibular glands of NSG mice and those histology was evaluated. PDX-derived organoid cells were evaluated for the presence of MYB-mediated fusion genes and proceeded for in vitro drug sensitivity assay. Human ACC-derived organoids were successfully generated in three-dimensional culture and confirmed the ability of these cells to form tumors by orthotopic injection. Short-term organoid cell cultures from two individual ACC PDX tumors were also established that maintain the characteristic MYBL1 translocation and histological features of the original parent and PDX tumors. Finally, the establishment of drug sensitivity tests on these short-term cultured cells was confirmed using three different agents. This is the first to report an approach for the generation of human ACC-derived organoids as in vitro and in vivo cancer models, providing insights into understanding of the ACC biology and creating personalized therapy design for patients with ACC. K E Y W O R D S drug sensitivity test, organoid culture, orthotopic transplantation, patient-derived xenograft (PDX) model, salivary adenoid cystic carcinoma 1 | INTRODUCTION Adenoid cystic carcinomas (ACC) is one of the most common types of salivary gland malignancies, representing approximately 1% of all head and neck malignancies and about 10% to 15% of all salivary gland cancers. 1,2 Salivary ACC generally represents as slow growth tumor, however, also

show abstract

Section: Resultsmentioning

confidence: 99%

“…We then tried to generate PDX ACC model as Cornett et al has reported previously. 25 As shown in Figure 1…”

Section: Generation Of Pdx Acc Modelmentioning

confidence: 90%

Establishment of PDX‐derived salivary adenoid cystic carcinoma cell lines using organoid culture method

Takada

Aizawa

Sano

et al. 2020

Intl Journal of Cancer

View full text Add to dashboard Cite

show abstract

“…For example, Mitani et al reported that the level of MYB expression in identical histological subtypes of ACC is associated with a shorter survival time. Recently, xenografting and the first MYB‐NFIB‐positive cell line (UM‐HACC‐2A) have been established and represent interesting tools to explore novel therapeutic possibilities . Therapeutically, MYB‐targeted antisense oligodeoxynucleotides (G4460; INX‐3001; LR3001) have not been effective in clinical trials ; however, several lines of evidence suggest that MYB is a promising therapeutic target .…”

Section: Discussionmentioning

confidence: 99%

Clinically Integrated Molecular Diagnostics in Adenoid Cystic Carcinoma

Thierauf

Ramamurthy

et al. 2019

The Oncologist

View full text Add to dashboard Cite

Background Adenoid cystic carcinoma (ACC) is an aggressive salivary gland malignancy without effective systemic therapies. Delineation of molecular profiles in ACC has led to an increased number of biomarker‐stratified clinical trials; however, the clinical utility and U.S.‐centric financial sustainability of integrated next‐generation sequencing (NGS) in routine practice has, to our knowledge, not been assessed. Materials and Methods In our practice, NGS genotyping was implemented at the discretion of the primary clinician. We combined NGS‐based mutation and fusion detection, with MYB break‐apart fluorescent in situ hybridization (FISH) and MYB immunohistochemistry. Utility was defined as the fraction of patients with tumors harboring alterations that are potentially amenable to targeted therapies. Financial sustainability was assessed using the fraction of global reimbursement. Results Among 181 consecutive ACC cases (2011–2018), prospective genotyping was performed in 11% (n = 20/181; n = 8 nonresectable). Testing identified 5/20 (25%) NOTCH1 aberrations, 6/20 (30%) MYB‐NFIB fusions (all confirmed by FISH), and 2/20 (10%) MYBL1‐NFIB fusions. Overall, these three alterations (MYB/MYBL1/NOTCH1) made up 65% of patients, and this subset had a more aggressive course with significantly shorter progression‐free survival. In 75% (n = 6/8) of nonresectable patients, we detected potentially actionable alterations. Financial analysis of the global charges, including NGS codes, indicated 63% reimbursement, which is in line with national (U.S.‐based) and international levels of reimbursement. Conclusion Prospective routine clinical genotyping in ACC can identify clinically relevant subsets of patients and is approaching financial sustainability. Demonstrating clinical utility and financial sustainability in an orphan disease (ACC) requires a multiyear and multidimensional program. Implications for Practice Delineation of molecular profiles in adenoid cystic carcinoma (ACC) has been accomplished in the research setting; however, the ability to identify relevant patient subsets in clinical practice has not been assessed. This work presents an approach to perform integrated molecular genotyping of patients with ACC with nonresectable, recurrent, or systemic disease. It was determined that 75% of nonresectable patients harbor potentially actionable alterations and that 63% of charges are reimbursed. This report outlines that orphan diseases such as ACC require a multiyear, multidimensional program to demonstrate utility in clinical practice.

show abstract

“…The research on adenoid cystic carcinoma (ACC), a rare relentless neoplasm arising in secretory glands, was limited by contaminated cell lines and traditional PDX, and a more accurate model system exhibiting important molecular features of this tumour was needed. To this end, Cornett and coworkers carried out the study published in this issue of EBioMedicine [8]. The group performed PDOX in salivary submandibular glands of immunodeficient mice and evaluated the fidelity of ACC during subsequent passages.…”

mentioning

confidence: 99%

“…Furthermore, genomic and molecular alterations unique to the original ACC were retained. Their data also demonstrates PDOX tumours as a sound model for drug testing [8].…”

mentioning

confidence: 99%

Orthotopic tumours, a hot topic for xenograft models?

Zheng

2019

EBioMedicine

View full text Add to dashboard Cite

Serial patient-derived orthotopic xenografting of adenoid cystic carcinomas recapitulates stable expression of phenotypic alterations and innervation

Cited by 14 publications

References 37 publications

Establishment of PDX‐derived salivary adenoid cystic carcinoma cell lines using organoid culture method

Establishment of PDX‐derived salivary adenoid cystic carcinoma cell lines using organoid culture method

Clinically Integrated Molecular Diagnostics in Adenoid Cystic Carcinoma

Orthotopic tumours, a hot topic for xenograft models?

Contact Info

Product

Resources

About