Treatment of NF1-Driven Neurofibromas Through VDR-Mediated Stromal Reprograming
Abstract
Virtually every patient diagnosed with neurofibromatosis is faced with the challenge of managing neurofibroma tumor growth.This can range from the emotional difficulties of cosmetically disfiguring dermal neurofibromas to the more painful growth of deep-tissue plexiform neurofibromas. In this proposal we took a new approach to target neurofibromatosis-associated tumors by breaking down their stromal support network. This work demonstrated a potent ability for nerve-associated fibroblasts to support resistance to MEK inhibition in association with activation of the PI3K/Akt pathway, supporting the therapeutic potential of stromal targeting therapies. To pursue this, we tested the ability for a clinically approved class of drugs that activate the vitamin D receptor (VDR) to promote therapeutic responses to MEK inhibition. We found that while VDR agonist was able to suppress markers of fibroblast activation in vitro, it had no impacts on tumor growth in vivo either as single agents or in combination with the MEK inhibitor selumetinib. Notably, this work did uncover a putative role for VDR activation in promoting tumor vascularization, a finding that has been associated with enhanced delivery and efficacy of chemotherapeutics in pancreatic cancer and is the focus of ongoing clinical trials. Future studies will be needed to see if the same observations can be extended to the treatment of neurofibromatosis-associated tumors.
Document Details
- Document Type
- Technical Report
- Publication Date
- Jan 01, 2024
- Accession Number
- AD1228197
Entities
People
- Michael R. Downes
- Morgan L. Truitt
- Ronald M. Evans
Organizations
- Salk Institute for Biological Studies