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

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. 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.