Open Proposal Program

The objective of this pilot study is to establish the reliability and accuracy of measurement of cutaneous neurofibromas (cNF) made using high frequency ultrasound (HFUS) and optical frequency domain imaging (OFDI).  The primary aim is to determine the intra-rater and inter-rater reliability of HFUS measurements of cNF volume at baseline.  Secondary aims are to:  1. Determine the intra-rater and inter-rater reliability of HFUS measurements of cNF volume growth over one year;  2. Determine the intra-rater and inter-rater reliability of OFDI measurements of cNF volume at baseline and over one year; 3. Determine the accuracy of HFUS and OFDI measurements by comparing them to caliper measurement and digital photographs.  Exploratory aims are to: 1. Determine the minimal size of cNF that is clinically visible on examination; 2. Calculate the average change in cNF volume over one year; 3. Assess patient-reported quality of life related to their cNF; 4. Test for correlations between cNF growth and demographic/clinical factors; 5. Establish an imaging and blood biobank for future research use.

Dr. Le proposes to establish the utility of this non-germline plexiform neurofibroma (pNF) model as a rapid preclinical therapeutic drug screening tool to identify effective therapies for pNF.  To achieve this goal, Le and his team will first explore the possibility of long term storage of DNSCs to maintain their tumorigenic potential for reliable and rapid plexiform neurofibromagenesis. Next, they will develop it into a robust plexiform neurofibroma model for preclinical drug screening by testing therapeutic effects of different pharmacological interventions.

Narrative: Read about the project’s background, goals, methods, preliminary data, and progress to date (auspices of Dr. Lu Le, Lu.Le@UTSouthwestern.edu)

Dr. Walker aims to identify putative proteomic and/or phosphoproteomic signatures associated with loss of NF1. Recent advances in mass-spectrometry (MS)-based proteomics permit the determination of the extent, localization, and site-specific stoichiometry of protein phosphorylation. We propose using two complementary MS-based approaches to define (i) the proteome and phosphoproteome and (ii) the activated kinome signature of NF1-deficient Schwann cells (SCs). Walker’s team will perform analyses on a panel of SC lines derived from PNs. Transcriptome profiling of cell lines will complement these data sets, together providing a detailed view of the cellular signaling networks and the molecular targets controlled by neurofibromin in a cell-type relevant to the disease. Finally, Walker’s team  will use small molecule inhibitors to both known and any novel signaling pathways we identify to examine the adaptive kinome in treated cell lines. Combining the use of a novel panel of cell lines with the sensitivity of high-end MS, they expect to identify signaling pathways and targets previously implicated as being important in NF1-associated tumors, as well as new and unexpected targets downstream of NF1.

Narrative: Read about the project’s background, goals, specific aims, and impact (auspices of Dr. James Walker, jwalker@helix.mgh.harvard.edu)

This project aims at investigating the possibility that hyperactive Ras/ERK signalling could contribute to pro-neoplastic metabolic rearrangements in mitochondria of neurofibroma cells by regulating TRAP1 chaperone activity, thus crucially contributing to the processes of growth and malignant transformation of PNs. Colombo and Rasola will dissect the mode of action of TRAP1, connecting it with the metabolic status of PNs and MPNSTs, which will be thoroughly investigated in in vivo tumor models.

Narrative: Read about the project’s background, goals, methods, and impact (auspices of Dr. Giorgio Colombo, giorgio.colombo@gmail.com; Dr. Andrea Rasola, andrea.rasola@unipd.it)

The primary goals of this project are (1) to set up in vitro conditions to efficiently differentiate iPS cells into cells of the Neural Crest-Schwann cell lineage, (2) to characterize the methylome and transcriptome of these cells with distinct NF1 genotypes and test their potential engraftment/tumor formation capacity, and (3)
to generate new iPSC and edit control iPSC with distinct NF1 genotypes to interrogate the presence of epigenetic memory in the PNF-derived iPS cells generated.

Narrative: Read about the project’s background, goals, methods, preliminary results, and progress to date (auspices of Dr. Edu Serra, eserra@igtp.cat)

The primary objective of this project is to evaluate whether patients receiving an Acceptance and Commitment Training (ACT) intervention demonstrate improved outcomes on a measure of pain interference (Pain Interference Index) when compared to a wait-list comparison group in adolescents and young adults with NF1 and PNs who experience chronic pain that interferes with daily functioning.

Narrative: Read about the project’s background, goals, preliminary results, and progress to date (auspices of Dr. Staci Martin, martins@mail.nih.gov)

This project’s primary goal is to determine the role of the Extracellular Matrix (ECM) in the neoplastic transformation of Schwann cells (SCs). The in vitro systems investigated will enable discovery of the ECM influence on Schwann cell progression toward malignancy in plexiform neurofibromas and its importance in/for drug screening.

Narrative: Read about the project’s background, goals, specific aims, and impact (auspices of Dr. Federica Chiara, federica.chiara@unipd.it)

The goal of this project is to evaluate the therapeutic efficacy of various AAV serotypes, a TGF- β inhibitor, a VEGF inhibitor and a VEGFR inhibitor against existing plexiform neurofibromas utilizing a novel genetically engineered mouse model of plexiform neurofibroma.  The studies being conducted are highly significant from both scientific and clinical standpoints because they will mechanistically dissect novel therapeutic targets for personalized treatment of NF1-deficient tumors such as plexiform neurofibromas.

Narrative: Read about the project’s background, goals, specific aims, and impact (auspices of Dr. D. Wade Clapp, dclapp@iu.edu)

The overall goals of this research are to : 1) Establish the durability of the effect of the combination of BRD4i + MEKi and also identify potential biomarkers, and 2) to determine whether EZH2 inhibition is an effective therapeutic approach.  The studies are highly significant because they will establish the durability of the BRD4/MEK combination enabling its advancement to the clinic, and help establish another target (EZH2) as a viable therapeutic approach.

Narrative: Read about the project’s background, goals, specific aims, and impact (auspices of Dr. Nancy Ratner, Nancy.Ratner@cchmc.org)

Dr. Ratner and her team hypothesize that Stat3 inhibition using a Stat3 Antisense RNA will prevent tumor formation.  Already, the  inhibitor, AZD 9150 / ISIS 481464 has shown efficacy in multiple myeloma and is in Phase1/1b trials in other cancers. This project will identify methods to prevent neurofibroma formation.  The impact of this project could allow for the rapid translation of early intervention to human patients.

Narrative: Read about the project’s background, goals, specific aims, methods, results and impact (auspices of Dr. Nancy Ratner, Nancy.Ratner@cchmc.org)

The goals of this project include: 1) To establish a biorepository of tissue, buffy coat, plasma and serum from patients with NF1 who are undergoing surgical removal of a lesion including a cutaneous neurofibroma, an atypical neurofibroma, a diffuse infiltrating neurofibroma, a plexiform neurofibroma, or an MPNST, 2) to genomically characterize banked samples, and 3) increase availability of these tissues to the research community. This project will improve access to tissue as a core tool to support discovery of new therapeutics for NF1 patients.

To learn more about this project, including the updated list of samples, and the SOP, click here. 

To make a request for samples, click here.

Narrative: Read about the project’s background, goals, specific aims, methods, results and impact (auspices of Dr. Christine Pratilas, cpratil1@jhmi.edu)

The main goal of this project was to determine if BRD4 inhibitors can prevent or delay the onset of tumors in a mouse model for MPNST development in NF1 microdeletion patients (NPS mice) and if the treatment with BRD4 inhibitors prevents the recruitment of immune cells to tumor initiation sites.

Narrative: Read about the project’s background, goals, specific aims, results and impact (auspices of Dr. Thomas de Raedt, tderaedt@rics.bwh.harvard.edu)

Jianqiang Wu, M.D., Ph.D. and Kakajan Komurov, Ph.D. (Cincinnati Children’s Hospital)

This project aimed to identify molecular signatures of Schwann cells and non-Schwann cells (macrophages, fibroblasts, mast cells and endothelial cells) to define the neurofibroma interactome and potential therapeutic targets for preclinical and clinical trials.

Narrative: Read about the project’s background, goals, methods, results, and impact (auspices of Dr. Jianqiang, Jianqiang.wu@cchmc.org; Dr. Kakajan Komurov, kakajan.komurov@cchmc.org)

Publication: Choi K, Komurov K, Fletcher JS, Jousma E, Cancelas JA, Wu J, Ratner N. An inflammatory gene signature distinguishes neurofibroma Schwann cells and macrophages from cells in the normal peripheral nervous system. Scientific Reports 2017 Mar; 7, 43315. doi:10.1038/srep43315

This project aimed to: (1) assess GCPII as a clinical pathologic marker to distinguish benign neurofibromas from malignant MPNSTs; (2) complete GCPII inhibitor pharmacokinetics and pharmacodynamics in Nf1flox/flox; Dhh-Cre mice; (3) evaluate effect of daily administration of a GCPII inhibitor on tumor progression in Nf1flox/flox; Dhh-Cre mice; and (4) assess effect of GCPII genetic knock out on neurofibroma tumor development in Nf1flox/flox; Dhh-Cre mice.

Narrative: Read about the project’s background, goals, specific aims, methods, results, and impact (auspices of Dr. Barbara Slusher, bslusher@jhmi.edu; Dr. Nancy Ratner, nancy.ratner@cchmc.org; Dr. Anat Stemmer-Rachamimov, astemmerrachamimov@partners.org)

This project aimed to identify molecular pathways that mediate rapid neurofibroma growth and/or response to therapy, using gene expression analysis of mouse neurofibromas followed by validation.

Narrative: Read about the project’s background, goals, specific aims, methods, results, and impact (auspices of Dr. Nancy Ratner, nancy.ratner@cchmc.org)