86. Whole genome sequencing of mouse derived cell-free DNA to develop a NF1-MPNST-PDX liquid biopsy model

Aly Abdelkareem

Paul Jones

Paul Jones is a graduate student in the laboratories of Aadel Chaudhuri and Angela Hirbe. His research interest is in understanding mechanism of MPNST formation and in detecting early MPNST transformation in patients and in vivo PDX models using a liquid biopsy assay. Through his graduate work he would like to develop a novel liquid biopsy assay to detect early MPNST formation, to profile high-risk NF1 patients at most risk for MPNST transformation and to develop a novel assay to detect malignancy in a PDX-MPNST model. He aims to continue to apply his skillset to better diagnosis and treat NF1-MPNST in subsequent post-doctoral work..  He is has a keen interest in academic teaching of undergraduates focusing on neurobiology and cancer biology. In terms of a future career, he would like to stay in academia and pursue an academic position with both teaching and research focuses.


Paul Jonesa, Wenjia Fenga, Xiaochun Zhanga, Peter Harrisa, Taylor Sundbyb, Faridi Qaiuma, Jack Shernb, Aadel Chaudhuria, Angela Hirbea

aWashington University, St. Louis, MO, USA; bNational Cancer Institute, Bethesda, MD, USA

Malignant peripheral nerve sheath tumors (MPNST) are an aggressive Neurofibromatosis Type 1 (NF1) associated sarcoma with few treatment options. Our lab has generated a series of patient-derived xenograft (PDX) mouse models to assess the efficacy of various treatments in vivo on human tumors. Longitudinal data collection is limited to gross tumor measurements, which fail to provide genomic information in the course of treatment, which may inform mechanisms of treatment resistance. To address this, we have begun to develop a NF1-MPNST-PDX liquid biopsy with the objective of non-invasively collecting sequential genomic data in response to targeted treatment. We have been able to longitudinally collect 50 uL of plasma from twenty-one mice bearing PDX without any effect on survival. Mean DNA from terminally collected samples yielded 1.12 ± 1.02 ng/uL plasma with a human cfDNA-like pattern with dominant DNA fragments between 70 and 450 bps in size on electropherogram. We performed whole-genome sequencing on a subset of this collected plasma and corresponding tumor (n=6) as described in our previous study on human cfDNA (Szymanski et al. 2021). This revealed that human-derived MPNST DNA is detectable and showed broad aneuploidy including a MPNST specific chromosome 8q gain. These findings suggest that cfDNA may be an informative precision biomarker that can be serially collected and analyzed to track tumor burden in NF1-MPNST-PDX models undergoing targeted drug studies.