Molecular Impact of Pharmacologic Therapies on NF1 Skeletal Disease
Abstract
Neurofibromatosis Type 1 (NF1) is a tumor-predisposing syndrome that affects multiple organ systems. With regard to the skeletal system, individuals with NF1 may have osteopenia (weak bones) or may develop scoliosis. Children with NF1 may present at birth or in early childhood with congenital tibial dysplasia (bowing of the lower leg). Treatment may involve bracing to support the bowed leg in hopes of preventing fracture. Unfortunately, the tibia often fractures. Unlike typical fractures in children without NF1, fractures of these bowed tibiae in NF1 often fail to heal despite numerous surgeries that may be performed over several years. And more often than in children without NF1, these persistent fractures (i.e. pseudarthroses) require amputation. Currently, proven effective treatments are lacking. Translational research into the pathogenesis and potential treatment of tumor manifestations in NF1 have led to numerous pharmacologic agents currently under investigation in clinical trials and to the FDA approval of selumetinib to treat non-operable plexiform neurofibromas in children. However, similar advances for skeletal manifestations in NF1 are lacking. Our laboratory is committed to understanding the genetic and molecular basis of NF1 skeletal disease, including NF1 fracture pseudarthrosis. The goal of our research program is to translate basic-science discoveries toward novel treatment paradigms. We and others have shown that, like NF1 tumors, NF1 fracture pseudarthroses are associated with somatic loss of the NF1 gene, which results in activation of molecular pathways that are also activated in NF1 tumors. Moreover, these pathways are targeted by pharmacologic agents currently in clinical trial, or already FDA-approved, for the treatment of NF1 tumors or related conditions. Thus, we recognize the potential for these pharmacologic agents to be repurposed to treat NF1-associated skeletal disease, including pseudarthrosis. This study explores the hypothesis that drugs currently in clinical trials for NF1 tumors, or other related conditions, can correct the molecular dysregulation that we have previously demonstrated in patient pseudarthrosis-derived primary cultured cells. As we have previously performed comprehensive molecular analyses in these patient-derived cells, the pharmacologic agents included in this study were selected based on their ongoing investigation in clinical trials and based on the molecular pathway they selectively target. Thus, the agents studied here were selected because they target and inhibit molecular pathways that we have already shown are activated in cells from patient pseudarthroses. By investigating the response of patient pseudarthrosis-derived cells to each of these compounds, we will develop novel hypotheses regarding the potential for these compounds to effectively treat NF1-associated fracture pseudarthrosis and, potentially, other skeletal manifestations in NF1.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210576
Entities
People
- Jonathan J. Rios
Organizations
- United States Army
- University of Texas Southwestern Medical Center