An Engineered Coculture System for NF1 Neurofibromas
Abstract
Type 1 Neurofibromatosis (NF1) is a widespread neurological disorder, with multi-system pathologies and a marked increased incidence of cancer. The birth incidence is approximately 1 in 3,500, of which about half are due to new mutations not present in either parent, and applies to all ethnicities and both sexes. It is the most common known genetic predisposition for both neurological problems and cancer development. Benign neurofibromas are tumors that are associated with peripheral nerves and arise in nearly all NF1 patients. Dermal neurofibromas can represent a significant burden on the quality of life, and plexiform neurofibromas bear the additional risk of potential nerve compression leading to paralysis and progression to malignant peripheral nerve sheath tumors (MPNSTs) that are a main cause of mortality. Because there is no established drug treatment, surgery is the only current option for patients with plexiform neurofibromas that are causing serious loss of function. Surgery itself can cause problems such as paralysis because the tumors grow along and around the nerves. Furthermore, the tumors often return and re-grow after surgery. The overall goal of this proposal is to develop a system that will allow accurate testing of potential drug treatments for NF1 neurofibromas in cultured cells. Most in vitro drug testing is performed on cells growing in two dimensions (2D) on plastic dishes. A better approach is to grow the neurofibroma cells together with other cell types that are typically associated with them, in samples derived from patients. We will co-culture these cell types, not on plastic dishes, but rather in a three-dimensional (3D) matrix that models the tumor environment. The advantages that we expect from this approach are that: (1) cells will adopt functions that closely mimic those present in the tumors; (2) the cell types will interact with each other as they do in the tumors; and (3) the response of the cells to the drug treatments will much more accurately predict whether the drugs will be successful when transferred into clinical trials. The development of a 3D co-culture model for NF1 neurofibromas may also provide benefits when compared to the animal models that are currently used for this purpose. Although elegant animal models for NF1 neurofibromas have recently shed light on drug candidates that are entering clinical trial, they are complex and very expensive and are not amenable to high-throughput screening. Thus, it seems unlikely that animal models will be sufficient to triage the large number of potential therapeutic agents, and combinations of those, to determine which should enter the clinic. We propose that an organotypic model of NF1 neurofibromas would be an extremely useful way to identify and screen these drug candidates. Successful development of the models that we propose would have a rapid impact on preclinical development and it would be reasonable to expect that it could influence the drug candidates entering clinical trial for NF1 neurofibroma treatment within 5 years. One of the difficulties that has prevented the development of an organotypic model for neurofibromas is how to include the nerve in the system because neurons tend to be difficult to culture. The Principal Investigator of this proposal, Dr. Sundararaghavan, is a biomedical engineer and new investigator with unique training and expertise in both cultured peripheral neurons and, more specifically, the development of nanofiber scaffolds that can model neuronal form and function. We have established a team of researchers for this project including an established NF1 investigator, Dr. Ray Mattingly, who also has experience in development of 3D co-culture models of breast cancer, an expert in human embryonic stem cells, Dr. Doug Ruden and a NF Clinician, Dr. William Kupsky. We propose using two separate approaches to include a neural component to produce the first 3D model of NF1 neurofibroma,
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 31, 2017
- Source ID
- W81XWH1610102
Entities
People
- Harini G Sundararaghavan
Organizations
- United States Army
- Wayne State University