Modeling NF2 Tumors for Drug Screening Using Induced Pluripotent Stem Cells
Abstract
Neurofibromatosis type 2 (NF2) is a genetic disorder and by age 60, 100% of patients develop tumors in the nervous system. The most common tumor being vestibular schwannoma, a tumor of the support cells (Schwann cells) insulating the vestibulocochlear nerve. Hearing loss is a common presenting symptom in adults due to compression of the auditory nerve, becoming life-threatening as the tumor impinges on the brain stem. Patients demonstrate considerable differences in the age of tumor onset, tumor growth, and response to drug therapies. Hence, modeling NF2 tumor growth using patient-relevant cells would be beneficial. Using NF2 patient skin cells, pluripotent stem cells can generated with induced pluripotent stem cell (iPSC) technology. Pluripotent stem cells can be expanded to generate more stem cells or differentiated into any cell type. In Aim 1, human iPSC lines will be generated using current technologies and differentiated into Schwann cell and endothelial cell (cells that form blood vessels) to model NF2 tumor growth and new blood vessel formation. The tumor environment consists of the nerve cells, schwannoma cells, and endothelial cells and is not typically cultured as a composite in vitro. Animal models are more sophisticated but are limited due to the species differences, for example, the drug Avastin binds to human, but not murine vascular endothelial growth factor (VEGF). The development of a 3D NF2 model using Schwann cell and endothelial cells would enable screening of novel drugs, as well as a better understanding of current and novel treatments, as proposed in Aim 2. Schwannomas are most commonly found on the vestibulocochlear nerve and less on the more distal, lower limbs. Neuronal activity is higher on the vestibulocochlear/cochlear nerve and fire at a much lower frequency for more distal limbs. It is not known what triggers Schwannoma formation on the vestibulocochlear nerve, but it has been suggested that the higher activity of the neurons may play a role. The response of Schwann cells to higher frequencies, as well as changes to NF2-Schwannoma cell interactions due to neuronal activity, is not known, but changes in Schwann cell secreted factors that could impact the formation of new blood vessels as well as Schwannoma proliferation are possible, and important to define. In Aim 2, the impact of electrical activity, approximating the electrical activity of the associated neurons in the vestibular schwannoma, in the Schwannoma/endothelial cell interaction will be investigated. Current treatment options are limited and chemotherapy is not appropriate for NF2 due to the slow tumor growth rate. Thus, there is a need for novel therapies with low toxicity, as patients tend to be younger and require treatments over a more extended timeframe. Bevacizumab (Avastin), a human vascular endothelial growth factor (VEGF) antibody, has exhibited efficacy in the clinic with 57% of patients showing significantly improved hearing (word recognition) and 55% exhibiting a significant reduction in tumor volume, and it is generally well tolerated. This drug blocks human-VEGF and improves some but not all NF2 vestibular Schwannomas. Differences in patient NF2 likely play a role, and we expect a combination of therapies will be needed to benefit more patients, especially those responding partially to anti-VEGF treatment alone. Human iPSC technologies now enable in vitro modeling of NF2 using human cells derived from individual patients to study their therapeutic response and to aid new drug identification. In Aim 3, Avastin and two other novel drugs not previously used in this context will be tested to determine their impact on NF2 angiogenesis and other aspects of tumor growth. This will be tested on models built from different individual patients as well as from Schwannoma and endothelial cells. Accomplishing these aims will lead to (1) the creation of novel NF2 iPSC lines that can be used to generate
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 29, 2016
- Source ID
- W81XWH1510152
Entities
People
- Sally Temple
Organizations
- SENS Research Foundation
- United States Army