Investigating Fibrogenic Response to MEK Inhibitor to Develop Synergistic Therapy for Neurofibroma
Abstract
Neurofibromatosis Type 1, or NF1, is an inherited neurological disorder that affects about 1 in 3,000 individuals worldwide. NF1 causes a variety of symptoms, including the development of benign (non-cancerous) tumors called neurofibromas. These hallmark tumors of NF1 consist of a variety of cell types including Schwann cells, fibroblasts, mast cells, macrophages, and endothelial cells, as well as extracellular components such as collagen. As the name implies, fibrosis is a hallmark feature of neurofibroma; up to 70% of the dry weight of neurofibroma is collagen, and a large portion of the cells in the tumor are fibroblasts. However, the contribution of these fibrotic components to neurofibroma tumorigenesis has remained largely unknown, both in the initiation and progression of neurofibroma and the response to therapeutic treatments. Mounting evidence has shown that fibroblasts interact with Schwann cells to affect Schwann cell function. Neurofibromas are divided into two main subtypes: (1) Cutaneous neurofibromas (cNFs) arise in the skin and can number from a few to thousands. More than 99% of individuals with NF1 will develop cNFs, which can cause itching and discomfort as well as emotional distress and social anxiety. (2) Plexiform neurofibromas (pNFs) develop deeper in the body along a nerve bundle, or plexus, and can cause pain, numbness, and weakness. More than 50% of NF1 individuals develop pNF. In about 8-13% of NF1 individuals, pNFs will transform into malignant peripheral nerve sheath tumors (MPNSTs), an aggressive tumor that is the leading cause of death in NF1 patients. The options for neurofibroma treatment are limited, with surgical resection currently the mainstay treatment option for both cNF and pNF. While drug therapies for cNF are still lacking, in 2020, the FDA approved selumetinib as the first drug to treat symptomatic, inoperable pNF. Selumetinib is an oral selective inhibitor of the enzyme mitogen-activated protein kinase (MEK), and it blocks the excessive activation of RAS/MAPK signaling pathway due to NF1 loss in tumor-originating Schwann cells. Although selumetinib provides encouraging clinical benefits to NF1 patients with inoperable pNF, and its FDA-approval was met with great enthusiasm by the NF community, there is still room for improvement. For example, while selumetinib treatment shrinks tumors, it does not completely eliminate them. Another significant issue is that selumetinib must be given continuously in order to achieve sustained response; interruption of drug treatment results in tumor regrowth. The underlying mechanisms that cause this regrowth remain unclear, but one possibility is that certain factors from cells in the tumor microenvironment are responsible. If this is the case, then targeting these microenvironment cells/factors would be a rational strategy to improve the efficacy of MEK inhibition. The broad objective of this proposal is to target the neurofibroma tumor microenvironment to improve MEK inhibitor-based treatment of pNF, as well as cNF. Since fibrosis is a hallmark feature of the neurofibroma tumor microenvironment, we hypothesize that combining inhibitors of fibrosis with MEK inhibitors can achieve a more effective and sustained therapeutic response in the treatment of pNF and cNF. If successful in our preclinical models, this novel treatment strategy would be readily available to test in clinical trials in human patients, as both treatments – MEK inhibitor and anti-fibrotic agents – are already FDA-approved.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210417
Entities
People
- Chunhui Jiang
Organizations
- United States Army
- University of Texas Southwestern Medical Center