Single Cell Analyses of NF1 Plexiform Neurofibroma and Atypical Neurofibroma in Human and in Mouse Models
Abstract
In NF1 patients, some plexiform neurofibromas are believed to develop into more aggressive tumors called atypical neurofibromas, and then into very aggressive sarcomas called MPNST. In this proposal, we use animal models of the three tumor types and human tumors. Our proposal is based on our finding that MEK inhibitors can shrink mouse and human neurofibromas, but sustained drug administration is required to maintain shrinkage, and some patients lose response. There is therefore an urgent need to identify alternative targetable pathways and biomarkers that predict more tumor shrinkage and tumor shrinkage that is sustained even when treatment is discontinued. Here, we propose to use a new method, single cell RNA sequencing, in mouse models and in human tumors. This method allows identification of all cell types in tumors and analysis of how pathways are changed in the specific cell types. This method will allow us to identify pathways that cooperate with MEK inhibition and biomarkers of response or lack of response in the specific cell types. We will also test whether another drug, a CDK inhibitor, is effective in any of the three tumor types. We predict that pathways will be identified for which drugs exist, and that these drugs can be tested in mouse models and, if successful, in human clinical trials. We also hypothesize that we will identify markers of response to drug or drug failure in both species. Such markers could be tested in preclinical trials in the next 3-5 years and used in clinical trials shortly thereafter.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Nov 19, 2019
- Source ID
- W81XWH1910816
Entities
People
- Nancy Ratner
Organizations
- Cincinnati Children's Hospital Medical Center
- United States Army