Developing Novel Biomarkers of Plexiform Neurofibroma Tumor Burden

PROJECT SUMMARY/ABSTRACT Neurofibromatosis type 1 (NF1) is a common inherited human disorder, with a frequency of approximately 1:2500 worldwide. A hallmark of NF1 is development of plexiform neurofibromas (PNFs) in 30 to 50% of NF1 patients. Currently, there are no biomarkers of tumor burden and whole body magnetic resonance imaging (MRI) is expensive and limited to few centers. We established an unbiased pipeline to identify candidate biomarker signals of tumor burden using plasma from neurofibroma-bearing DhhCre;Nf1fl/fl mice using untargeted metabolomics. Our preliminary data show that glucosylceramide (GC) is the most significantly deregulated compound in plasma from neurofibroma-bearing DhhCre;Nf1fl/fl mice. We developed a novel targeted mass spectrometry method to accurately quantify multiple elevated GC and lactosylceramide (LC) species. Further analysis of these candidate tumor burden biomarker signatures in plasma from NF1 individuals with PNFs and DhhCre;Nf1fl/fl mice stratified by tumor volume showed a preliminary strong correlation. In this proposal, we will combine the clinical and research infrastructure of the NF1 comprehensive program with the advance imaging and mass spectrometry capabilities of Cincinnati Children's Hospital Medical Center. Taking advantage of our large, well-characterized, Cincinnati Children’s NF1 population and the RASopathies biorepository, we propose to perform analytical validation studies of candidate GC/LC biomarker signature of tumor burden in plasma from NF1 patients and neurofibroma-bearing mice with defined numbers of PNF (tumor burden) by whole body MRI. The potential outcomes of our study are identification of candidate biomarker of tumor burden that contribute to patient risk stratification, and analytical validation of GC/LC biomarker signature (context of use). Collectively, this work represents a synergistic approach for discovery and validation of biomarkers of tumor burden in NF1.