# Neurofibromatosis Type 1 and the Search for Effective Tumor Therapies Using High-Throughput Drug Screening

## TL;DR

This review summarizes 50 years of drug screening for Neurofibromatosis Type 1, focusing on how high-throughput methods have advanced treatment discovery.

## Contribution

The paper provides a comprehensive review of high-throughput drug screening efforts for NF1, highlighting variability and future directions.

## Key findings

- High-throughput screening has informed clinical trials for NF1-related tumors.
- Variability in models, libraries, and methods complicates comparison across studies.
- Early RAS pathway targeting efforts preceded modern screening technologies.

## Abstract

In this review, we examine five decades of drug screening efforts aimed at developing treatments for Neurofibromatosis Type 1 (NF1). We begin with an overview of the clinical manifestations of NF1, followed by a discussion of early attempts to target the RAS pathway before the advent of high-throughput screening technologies. Next, we describe the in vitro and in vivo models employed in these studies and summarize the major screening efforts conducted across various NF1-related cell types, including any subsequent validation or follow-up studies. We conclude with a brief assessment of how high-throughput screening has informed clinical trials and discuss future directions for therapeutic discovery in NF1.

Neurofibromatosis type 1 (NF1) is a complex, multisystem, genetic disorder caused by germline NF1 variants that predispose affected individuals to tumors of the nervous system. With the identification of the NF1 gene in the late 1980s and the elucidation of the role of the encoded protein, neurofibromin, in regulating RAS signaling, considerable research effort has been invested to identify therapeutic treatments for NF1 tumors. Over the past two decades, high-throughput drug screening approaches have been a significant component of these endeavors. However, considerable variability exists among studies in terms of disease models, symptom targets, screening libraries, methods, and outcomes. In this review, we present an overall summary of efforts toward discovering new therapeutic strategies for NF1-related tumors using high-throughput screening and how such findings can be employed for prospective research in the NF1 field.