Elizabeth Schorry, MD
As a member of the national NF (Neurofibromatosis) Clinical Trials Consortium, we completed three phase II clinical trials of MEK inhibitors for treatment of plexiform neurofibromas, in children and adults with Nuerofibromatosis type 1 (NG1). An initial trial of the MEK inhibitor Selumetinib for children with NF1 and large plexiforms, led by the National Cancer Institute, showed significant volumetric shrinkage of tumors in 70% of participants. Similar trials in adults, but using different drugs (Cabozantinib, Pfizer drug PD0325901), showed shrinkage in 40% of patients. This has major implications for future management of these benign tumors which can cause significant morbidity and even mortality. In addition, identifying a class of drugs which hits the target for NF1 may enable treatment for other NF1 complications in the future, including bone disease, dermal neurofibromas, and even learning disabilities.
In addition, we collected data and described the pain experience in patients with NF1, including sources of pain, chronicity, frequency, pain interference, and associations of pain in a broad NF1 population. We participated with a group from NIH in modifying and validating standard measures of pain in an NF1 population. Documentation of improvement in pain and other functional measures in patients on NF clinical trials is an important requirement of the FDA. In addition, this is an underexplored area of NF1 which will have implications for future evaluation and management of patients.
Xueguang Sun, PhD
Dr. Xueguang Sun’s research interests focuses on developing the genomic tools and methods for epigenetic analysis. Since joining Cincinnati Children's Hospital Medical Center as director of the DNA Sequencing and Genotyping Core
in June 2016, he has been working towards establishing a more comprehensive sequencing platform to support the genomic studies in both basic and clinical research. During the last year, his lab developed a novel method for genome wide DNA methylation analysis. More recently, the lab applied this method to the single cell level by working together with the Flow Cytometry Core. Unlike bulk assays, measurements of heterogeneity through single-cell assays provide superior phenotypic resolution and do not require prior knowledge of the subtypes of cells within a sample. These measurements allow de novo identification of cell types within tissues and detection of biomarkers in rare cell types. An additional use it to identify heterogeneous responses or to compare cell states between complex samples without requiring prior knowledge of their population structure. His lab is trying to expand the methodology for analyzing other epigenetic markers such as 5-hydroxymethylcytosine.
Melanie Myers, PhD, MS
Dr. Melanie Myers
and colleagues have enrolled 163 adolescent/parent dyads into a longitudinal, mixed methods study to understand the factors that influence dyads’ choices about the type of genomic results they want to learn about the adolescent and their responses to learning results based on their choices. Adolescents without a clinical indication and their parents have prospectively made independent decisions about learning the adolescent’s genomic results for conditions that are preventable, treatable, or adult-onset, as well as for learning carrier-status for autosomal recessive conditions. While adolescents chose to learn fewer results for themselves than parents chose for the adolescents, all dyads came to consensus about what results to learn. As returned results come in we are measuring responses to learning the results. Supported through the National Institutes of Health funded eMERGE III (electronic medical records and genomics) study (U01HG8666 John Harley, PI), our data will also contribute to network-wide return of results aims and lessons learned across 10 institutions. As Dr. Myers and colleagues are the first to prospectively offer healthy adolescents/ parent dyads choices about learning genomic sequencing results, these findings will address a serious gap in the scientific literature and contribute to policies about engaging adolescents in decisions when learning genomic results is possible.
William Nichols PhD
Dr. William Nichols’
research efforts continue to focus on the genetics of pulmonary arterial hypertension (PAH). As part of a multinational effort to identify common genetic variation contributing to PAH susceptibility, whole genome single nucleotide polymorphisms (SNP) data generated for 700 idiopathic PAH patients of European descent selected from over 2800 group 1 PAH patients enrolled through the National Heart, Lung, and Blood Institute funded (HL105333) National Biological Sample and Data Repository for PAH (aka PAH Biobank) established here at Cincinnati Children's Hospital Medical Center contributed to an international genome wide association study (GWAS). Researchers performed two separate GWAS discovery analyses across 11,744 individuals of European ancestry including 2,085 patients with idiopathic PAH, one using primarily the genotype data of the 700 PAH Biobank subjects and the other using whole genome sequencing data of 850 subjects recruited primarily in the UK. The remaining subjects included were from France and Germany. Two loci associated with PAH reached genome wide significance in both discovery analyses. One locus was upstream of SOX17 which encodes the transcription factor SRY-related HMG box 17. The second was within HLA-DPA1/DPB1 in the HLA locus. Meta-analysis including all 2085 subjects confirmed the two loci and identified no additional loci at genome-wide significance. While previous genetic studies only identified rare genetic variants in several genes contributing to disease susceptibility, this is the first finding of common genetic variation at two different loci involved in the disorder. Ongoing studies will further refine the genetic regions as well as determine functional significance of these two genes.