Project Details
Description
Project Summary/Abstract
Neurofibromatosis type 1 (NF1) syndrome is an autosomal dominant cancer-predisposing syndrome afflicting
~1 in every 3,500 persons worldwide with the majority of patients developing benign plexiform and/or dermal
neurofibromas. Plexiform neurofibromas constitute a lifelong source of disfigurement, morbidity and mortality,
and have the potential to transform to a malignant peripheral nerve sheath tumor (MPNST), an aggressive soft
tissue sarcoma. In fact, approximately 15% of NF1 patients develop poor prognosis MPNSTs, often in the
second or third decade of life. Treatment options for MPNSTs are limited to complicated surgical procedures
and classical chemotherapy and, so far, molecular targeted therapies have demonstrated limited efficacy. We
desperately need new treatment options for the MPNSTs and methods to prevent them from development. It
was recently found that plexiform neurofibromas progress to MPNST via an intermediate, “atypical”
neurofibroma (ANF) that in 70% of tumors shows heterozygous or homozygous loss of CDKN2A the gene
encoding p16INK4a and p14ARF (Beert et al., 2011; Pemov et al., 2018). Our proposal will address critical unmet
needs in this field, including better in vitro and in vivo models of ANF and identification of critical vulnerabilities
of these cells. To provide a model for preclinical testing and prevention of ANF to MPNST development, we
combined Desert hedgehog (Dhh)-Cre driven biallelic deletion of Nf1 with heterozygous loss of Cdkn2a,
creating a unique model of transplantable ANF developing within pre-existing neurofibroma (Chaney et al.,
submitted). We also combined Dhh-Cre driven biallelic deletion of Nf1 and Pten, generating rapidly developing
perinatal ANF-like lesions (Keng et al., 2012). ANF from Dhh-Cre;Nf1fl/fl;Cdkn2a+/- mice grafted
subcutaneously into immunocompromised hosts grew, after a delay, providing a more rapid, tractable,
transformation system. We plan a complete transcriptome and exome analysis in these models (Aim 1a), and
further investigate the model by identifying and validating cell populations and markers altered in mouse
and human PNF, ANF, and MPNST in unperturbed tissue sections using a new image analysis
method called CO-Detection by IndEXing (Aim 1b). Modulation of the immune environment is increasing
used therapeutically. We will therefore define the influence of the nerve microenvironment and immune system
on progression from ANF to MPNST (Aim 1c). To identify ANF vulnerabilities, we have completed drug and
CRISPR-based genetic synthetic lethality screens in isogenic immortalized human Schwann cells that are NF1
wildtype or were made homozygous for NF1 loss of function mutations using gene editing. Candidate drugs
that inhibit PP2A, and other novel targets from the drug screening effort, will be tested for their effects in ANF-
like cells in vitro (Aim 2a) and, when successful, in our unique GEMMs (Aim 2b). Similarly, our genetic
screening effort will be used to define additional vulnerabilities tested in vitro (Aim 2c) and in vivo (Aim 2d).
Status | Active |
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Effective start/end date | 9/1/20 → 6/30/24 |
Funding
- National Institute of Neurological Disorders and Stroke: $587,214.00
- National Institute of Neurological Disorders and Stroke: $577,428.00
- National Institute of Neurological Disorders and Stroke: $571,785.00
- National Institute of Neurological Disorders and Stroke: $582,915.00
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