Targeting Fibrosis in Neurofibroma to Reduce Tumor Mass and to Enhance Its Response to MEK Inhibitor
Abstract
The tumor predisposition von Recklinghausen’s Neurofibromatosis type I (NF1) is one of the most common genetic disorder of the nervous system, affecting 1 in 3,000 individuals. Neurofibroma is the most common tumor in NF1 and typically presents as a disorganized nerve structure composed of proliferative neoplastic Schwann cells (NFSC) mix with neurofibroma-associated fibroblasts (NFAFs) in an abundant collagen matrix. In fact, collagen constitutes more than 50% of the tumor’s dry weight. Cutaneous neurofibromas (cNF) are disfiguring and greatly affect patients’ quality of life. Patients with plexiform neurofibromas (pNF) have a 10% lifetime risk of developing malignant peripheral nerve sheath tumors and their unusual capacity for growth can be life-threatening by their physical impairment of organ or neural function. The NF community this year celebrates the first FDA approval of the MEK inhibitor Selumetinib for certain types of pNF. Although this approval came as good news for patients and NF1 specialists, such as Dr. Le, who manage a large number of NF1 patients, the responses of pNF to MEK inhibitor are heterogeneous and not complete. This is likely because Selumetinib mainly targets the neoplastic Schwann cells, which compose only a small portion of the neurofibroma, whereas the fibroblast and collagen matrix in the tumor microenvironment comprise the big bulk of the tumor mass. Thus, additional therapy targeting the fibrosis and collagen in the tumor microenvironment in combination with Selumetinib are required to substantially reduce the tumor mass. However, despite the initial report by Dr. von Recklinghausen more than 138 years ago pointing to collagen and fibrosis as major components of neurofibroma (and hence he coined the name neurofibroma), their role has remains elusive. In fact, little is known about the mechanisms on how collagen and fibroblast mediate the initiation and progression of these tumors. This research proposal will fill this scientific gap and unmet medical need in neurofibromatosis research and clinical care to elucidate the mechanisms by which fibroblasts and fibrosis affect neurofibroma formation. Recent work in our laboratory has identified the developmental cells of origin for cutaneous and plexiform neurofibroma and generated novel models for these complex NF1-associated tumors. These studies also provide evidences that additional signals from the tumor microenvironment, including fibroblasts and collagen, play essential roles in neurofibroma formation. Leveraging our recently developed and fast turnover assays modeling neurofibroma in vitro and in vivo, as well as our characterization of the first specific neurofibroma-associated fibroblast marker, we propose to systematically address the absolute requirement of NFAFs and collagen for neurofibroma development. Since there is a wide array of clinically approved drugs already effectively targeting collagen-secreting fibroblasts in fibrosis and cancer context, demonstrating the critical role of fibroblasts and collagen for neurofibroma development in vivo will pave the way to additional new treatment options for NF1 patients, where no curative therapy exists today.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110651
Entities
People
- Lu Q Le
Organizations
- United States Army
- University of Texas Southwestern Medical Center