New Targets, Smarter Combinations: Six Projects Advance NF Drug Discovery

The Children's Tumor Foundation (CTF) is investing approximately $1.2 million in six new Drug Discovery Initiative (DDI) Awards to advance potential treatments for neurofibromatosis and schwannomatosis.

The 2026 projects take on some of the most persistent barriers to treating NF: overactive cell-growth signals, aggressive tumors that are difficult to detect and target, and the metabolic strategies tumors use to survive. Researchers are developing entirely new therapeutic molecules, repurposing a shelved drug, combining treatments to attack tumors from multiple directions, exploring more precise ways to detect and treat malignant peripheral nerve sheath tumors (MPNSTs), and accelerating how they evaluate potential therapies.

This year's DDI projects highlight how advances in NF biology are driving the discovery and development of new treatments, from identifying promising drug targets to evaluating potential therapies and uncovering new strategies to treat NF.

Development and Use of a RAS-GAP Glue in NF1

Jonathan Chernoff, MD, PhD, The Research Institute of Fox Chase Cancer Center

The NF1 gene normally produces neurofibromin, a protein that helps regulate RAS signaling, the system of cell-growth messages that tells cells when to grow and divide. When neurofibromin is lost, RAS can remain overactive and contribute to tumor development. Other proteins can also turn off RAS, but not effectively enough to compensate for that loss.

This team is developing a new type of "molecular glue" designed to connect RAS with one of these alternative regulators, p120RasGAP, and shut down overactive signaling. Using artificial intelligence and machine learning, the researchers have identified two promising candidates. They will now confirm how the glues work and use additional rounds of AI-guided development to optimize them, potentially establishing an entirely new therapeutic approach for NF1.

Repurposing the Shelved DGAT1 Inhibitor Pradigastat for NF1-Associated Tumors

Daochun Sun, PhD, Medical College of Wisconsin

NF1-associated tumors take in large amounts of fat and use an enzyme called DGAT1 to package the excess into lipid droplets, protecting tumor cells from harmful buildup. Lipid storage in macrophages-immune cells within the tumor environment-may also help tumors grow.

The researchers will test whether blocking DGAT1 with an experimental drug called pradigastat can disrupt this process and slow tumor growth. Because pradigastat is a shelved drug and has already been studied in people for non-cancer conditions, information is available about its safety, dosing, and activity in the body. Repurposing it could therefore shorten the path toward clinical testing if the approach proves effective.

HEMO as a Biomarker and Target for Malignant Peripheral Nerve Sheath Tumors

David Largaespada, PhD, University of Minnesota-Twin Cities

MPNSTs are aggressive cancers that can be difficult to detect early and treat once they recur or spread. This team is studying HEMO, a protein found on NF1-associated MPNST cells. Preliminary findings suggest that HEMO is elevated in the blood of people with MPNST, where it could potentially be used to detect or monitor tumors. Part of the protein also remains on the tumor-cell surface, creating a possible treatment target.

The researchers will develop nanobodies-small, highly specific antibody-like proteins-that recognize different portions of HEMO. These could form the basis of a blood test and be incorporated into immune-based treatments designed to direct immune cells toward MPNST cells. The project could advance two urgent goals: earlier detection and more precise treatment.

Targeting MPNST by Combining RAS Pathway Inhibitors with a Dual-Warhead CoREST Complex Antagonist

Philip Cole, MD, PhD, Brigham and Women's Hospital

Surgery remains the primary treatment for MPNST, but complete removal is not always possible when tumors are large, located near complex nerve networks, or have spread.

This team has identified the CoREST complex as a potential therapeutic target and developed corin, a small-molecule inhibitor with a "dual warhead" that blocks two enzymes within the complex simultaneously. In preliminary studies, corin killed MPNST cells when combined with several RAS pathway inhibitors. The researchers will test this strategy across multiple MPNST models and investigate why the drugs work more effectively together, building evidence that could help advance the combination toward clinical trials.

Deploying a quantitative multiparametric platform to evaluate metabolic reprogramming as a therapeutic strategy for NF2-related schwannomatosis in vivo.

Andrea I. McClatchey, PhD, Massachusetts General Hospital

Schwannomas are highly adaptable tumors that can use different survival strategies in response to their surroundings or treatment. This metabolic flexibility may be connected to the normal behavior of Schwann cells, which change how they use and provide nutrients while insulating nerves or responding to injury.

The researchers have developed a platform that can evaluate potential treatments in a widely used mouse model quickly and efficiently. It measures multiple indicators of drug performance and uses advanced imaging to show how individual tumor cells respond. The team will use the system to test metabolism-targeting drugs already being developed for other diseases, potentially revealing new vulnerabilities in schwannomas and helping prioritize promising treatments for further development.

Determining the Metabolic Consequences of PRMT5 Inhibition in MTAP-Deleted NF1-MPNST to Inform Therapeutic Combinations

Kathryn Lemberg, MD, PhD, Johns Hopkins University School of Medicine

MTAP, a gene involved in how cells use nutrients, is frequently deleted or mutated in NF1-associated MPNST. This may make the tumors vulnerable to PRMT5 inhibitors, a new class of drugs being developed for other cancers.

The researchers will test a new-generation PRMT5 inhibitor in multiple MTAP-deleted MPNST models, examine how it changes tumor-cell metabolism, and combine it with other drugs that block nutrient pathways. The most promising combinations will then be evaluated in patient-derived tumor models for their effects on tumors and potential side effects. The goal is to build evidence supporting future clinical trials for pediatric and young adult patients with MPNST.

Moving Promising Ideas Toward Treatments

CTF's Drug Discovery Initiative supports research with the potential to generate or advance new therapeutic approaches for neurofibromatosis and schwannomatosis. By investing in rigorous early-stage development, DDI helps researchers test bold ideas, build the evidence behind promising therapeutic strategies, and prepare them for the next stages of the treatment-development process.

The 2026 projects reflect the range of approaches needed to change what is possible for people living with NF-from creating entirely new types of therapeutic molecules to finding smarter ways to detect tumors, target cancer cells, test drug combinations, and evaluate potential treatments more quickly