Developing Biomarkers of Plexiform Tumor Burden in Patients With Neurofibromatosis-Type 1

Study Overview
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Brief Summary
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The purpose of this study is to identify tumor biomarkers in individuals with Neurofibromatosis type 1 (NF1). Biomarkers are signals that the investigator can measure that tell us about a process such as progress of a disease or treatment. Individuals with this diagnosis are at an elevated risk of developing a type of tumor called a plexiform neurofibroma. Currently, detecting the risk factors of these tumors in children is difficult and requires whole body imaging. The NF1 team at Lurie Children's established a way of using blood plasma in mice with neurofibromatosis type 1 to identify biomarkers that might signal the presence of tumors in people with NF1. This study is an effort to create biomarker profiles of patients with NF1 with known tumors. The study team will utilize whole-body MRI and mass spectrometry (a method for identifying unknown compounds and the properties of molecules). The ultimate goal of this study is to better understand the tumor biomarkers in patients with NF1.

Detailed Description
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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. The investigator 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. The investigator developed a novel targeted mass spectrometry method to accurately quantify multiple elevated GC and lactosylceramide (LC) species. In this proposal, the investigator will combine the clinical infrastructure of the NF1 comprehensive program and advance imaging at Ann & Robert H. Lurie Children's Hospital of Chicago with the mass spectrometry capabilities at Cincinnati Children's Hospital Medical Center. Taking advantage of our large, well-characterized, Lurie Children's NF1 population, the investigator propose to perform analytical validation studies of candidate GC/LC biomarker signature of tumor burden in plasma from NF1 patients 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.

Official Title
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Developing Novel Biomarkers of Plexiform Neurofibroma Tumor Burden

Conditions
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Neurofibromatosis 1, NF1, Neurofibromatosis Type 1

Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 1. Individuals with known diagnosis of neurofibromatosis type 1 (NF1) Exclusion Criteria: Patient does not meet NF1 diagnostic criteria Mosaic NF1 individuals Pregnant at Screening Patients who do not have the ability/capacity to undergo the informed consent process OR whose parent/legal guardian is unable to undergo the informed consent process.
Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Determine if glucosylceramide (GC) and lactosylceramide (LC) species levels correlate with tumor burden in patients with NF1 | The investigator and team will collect blood samples from individuals with NF1 stratified plexiform tumor (PNF) burden (none, small, intermediate, and large) versus age and sex matched healthy control. | 1 year | 
| Test if tumor burden correlates with GC and LC signature in individuals with NF1 who are undergoing clinical treatment with MEK inhibitors | The investigator and team will enroll 20 individuals with NF1 and inoperable PNFs in treatment with MEK inhibitors to correlate biomarker with tumor burden changes with therapy. | 1 year | 
| Assemble a longitudinal cohort of individuals with NF1 with plexiform neurofibromas (n=100) for deep phenotyping and tumor burden response to MEK inhibitors | Whole-body MRI at baseline and at time of annual visit (9-to-18-month intervals) will be used to deeply phenotype individuals based on tumor burden and tumor volume. Individuals will undergo plasma collection and clinical history assessment (medications, diet log, supplements, and anthropometric measurements) at each visit. For patients undergoing treatment with MEK inhibitors, a sample prior to treatment will be collected during this study. | 1 year | 
| Determine if glucosylceramide (GC) and lactosylceramide (LC) signature correlates with plexiform neurofibroma burden change in longitudinal cohort of 100 individuals with PNFs | The investigator and team will test GC/LC levels using validated mass spectrometry target method for quantification of these biomarkers. | 1 year | 
| Tumor volumetric analysis will be performed to correlate with GC/LC monitoring biomarker signature | GC/LC biomarker thresholds (cut-off) will be refined to evaluate predictive ability to identify individuals with large tumor burden. Tumor burden will be measured from whole-body MRI analysis with post-imaging processing software. | 1 year | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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NF1, Plexiform neurofibromas, neurofibromatosis type 1, neurofibromas