Funded Research
Testing immune modulation therapeutics and MEKi in neurofibroma
Dr. Nancy Ratner, Cincinatti Children's
My laboratory focuses on identifying therapies that to treat neurofibromatosis. We use a model in which tumors form, and test therapies to determine if they shrink tumors. If they do shrink tumors, we then test if shrinkage is maintained once the drug is removed. Recent studies show that the mouse tumors in our model accurately mimic human tumors (neurofibromas). Both contain large populations of tumor cells, which is expected, and contain large numbers of cells of the immune system, which is less expected. Therefore, we are targeting both tumor cells and immune cells using combination therapies. In this study, we will test an agent known to shrink tumors, a MEK inhibitor, together with an antibody that targets a major modulator of immune system function. If this combination therapy is effective, in the future doctors can test if the same combination therapy is effective in children or adults with neurofibromatosis.
Pharmacologic restoration of neurofibromin for the treatment of NF1-associated
Dr. Wade Clapp, Indiana University
Fifty to seventy percent of individuals with NF1 exhibit symptoms of attention deficit hyperactivity disorder (ADHD), resulting in substantial deficits related to school performance and social engagement. Similarly, there is a marked increase in traits characteristic of autism spectrum disorder (ASD), with 30-50% of patients with NF1 exhibiting features compared with 1%–3% of the general population. Our lab focuses on the development and evaluation of therapies for the treatment of these NF1-associated neurocognitive challenges. To do this, we use a mouse model that lacks one copy of the NF1 gene and exhibits the learning, attention, and behavioral challenges similar to those experienced by adults and children with NF1. Recent work by our lab found that we might be able to treat NF1-associated neurocognitive deficits by restoring functional levels of neurofibromin, the protein produced by the NF1 gene and that is decreased in patients with NF1, by preventing its degradation. Within the cell, the degradation of neurofibromin is regulated by the placement of a “tag,” which alerts the degradation machinery within the cell. One way to prevent proteins like neurofibromin from being degraded is to prevent this tagging process. In this study, we will evaluate the ability of drugs that inhibit this tagging process to restore levels of neurofibromin and rescue the neurodevelopmental deficits in mice with NF1. If these therapies are successful, physicians can evaluate these agents in children and adults with NF1-associated neurocognitive deficits.
Identifying regulators of neurofibromin activity
Dr. Harish Vasudevan, UCSF
The primary biochemical function of neurofibromin is to turn off RAS. However, there are currently no treatments that directly target neurofibromin’s regulation of RAS proteins. We recently found that KRAS appears to be the primary target of neurofibromin. Building on this observation, this study will identify ways to increase neurofibromin’s regulation of KRAS. Successful completion of this project has the potential to develop treatments that could be used to boost neurofibromin activity in people with NF-1.
Improving light-based therapy for NF1 tumors
Dr. Kavita Sarin, Stanford University
This project aims to develop a non-invasive, clinic-ready approach to improve treatment options for cutaneous neurofibromas (cNFs), present in the majority of persons with Neurofibromatosis Type 1. The team is exploring whether enhancing the delivery and effectiveness of light-based therapy, already widely used in dermatology, can provide a gentler alternative to surgery or lasers. Early laboratory work will evaluate whether this strategy can increase tumor cell response to treatment. If successful, this research could lay the groundwork for a future outpatient therapy that treats multiple cNFs at once, avoids scarring, and helps patients better manage tumors as they develop over time.