Abstract
BackgroundPredictive preclinical models play an important role in the assessment of new treatment strategies and as avatar models for personalised medicine; however, reliable and timely model generation is challenging. We investigated the feasibility of establishing patient-derived xenograft (PDX) models of high-risk neuroblastoma from a range of tumour-bearing patient materials and assessed approaches to improve engraftment efficiency.MethodsPDX model development was attempted in NSG mice by using tumour materials from 12 patients, including primary and metastatic solid tumour samples, bone marrow, pleural fluid and residual cells from cytogenetic analysis. Subcutaneous, intramuscular and orthotopic engraftment were directly compared for three patients.ResultsPDX models were established for 44% (4/9) of patients at diagnosis and 100% (5/5) at relapse. In one case, attempted engraftment from pleural fluid resulted in an EBV-associated atypical lymphoid proliferation. Xenogeneic graft versus host disease was observed with attempted engraftment from lymph node and bone marrow tumour samples but could be prevented by T-cell depletion. Orthotopic engraftment was more efficient than subcutaneous or intramuscular engraftment.ConclusionsHigh-risk neuroblastoma PDX models can be reliably established from diverse sample types. Orthotopic implantation allows more rapid model development, increasing the likelihood of developing an avatar model within a clinically useful timeframe.
Highlights
Predictive preclinical models play an important role in the assessment of new treatment strategies and as avatar models for personalised medicine; reliable and timely model generation is challenging
Establishment of high-risk neuroblastoma patient-derived xenograft (PDX) models Tumour samples were obtained from two consecutive groups of patients: newly diagnosed high-risk neuroblastoma patients from Sydney Children’s Hospital, Randwick and patients at the point of relapse from either Sydney Children’s Hospital Randwick or Children’s Hospital Westmead (Table 1)
This study extends previous neuroblastoma PDX model establishment reports[19,20,21,22,23,24,25,26,27,28] by demonstrating that PDX models can be developed from diagnostic cytogenetic culture without additional loss of fidelity, that more rapid engraftment can be achieved with orthoptic implantation and that additional sample processing can circumvent loss of models by xenogeneic graft versus host disease (GvHD)
Summary
Predictive preclinical models play an important role in the assessment of new treatment strategies and as avatar models for personalised medicine; reliable and timely model generation is challenging. The cure rates of children with high-risk neuroblastoma remain less than 50%3 and as low as 10% for relapsed and refractory disease.[4] Treatment-related acute toxicities and the high prevalence of significant late effects present major challenges.[5,6] Realistic laboratory models that reflect the genetic diversity of high-risk neuroblastoma have an important role to play in preclinical assessment of new agents or combinations, in validating the relevance of mutations as actionable targets and in modelling the development of drug resistance.[7,8] For the individual patient, personalised or avatar models are playing an increasingly important role in personalised oncology.[9,10]. Limited engraftment success rates, lengthy model establishment time and high maintenance costs all pose major challenges to the routine use of PDX models for personalised therapy.[11,18] Optimising the methodology to improve engraftment efficiency is critical for meeting urgent clinical needs in the era of personalised medicine
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