For schwannomatosis, that work is happening now, across multiple research groups and multiple pathways. Most of it will never make the news. Some of it may become the next trial on the list above.
What follows is drawn from published research literature. We will add conference presentation findings as they become publicly available.
How Researchers Test Treatments Before Human Trials
Two model organisms are central to SWN pre-clinical research. Zebrafish (Danio rerio) develop quickly, can be genetically modified to knock out SWN-related genes, and are transparent — researchers can watch tumor development in real time. A drug that suppresses schwannoma-like growth in zebrafish in 48 hours can be compared against hundreds of other candidates simultaneously. NF2-knockout zebrafish models have been the most widely used because NF2 was the first SWN gene characterized. Drug screening results from those models are the starting point — not the finish line — for whether a compound is worth pursuing across all SWN subtypes.
Mouse models are the second tier. Conditional knockout mice — where a SWN gene is switched off specifically in Schwann cells — reliably develop schwannomas. NF2-conditional knockout mice, which develop vestibular schwannomas, have been the standard testing ground for most of the compounds below. Conditional SMARCB1 knockout models also exist and are used in schwannomatosis research, though the published literature on them is thinner. Building out SMARCB1 and LZTR1 pre-clinical models is an active need in the field.
The Hippo Pathway — YAP / TAZ
Merlin — the protein encoded by the NF2 gene — is a key regulator of the Hippo tumor suppressor pathway. When merlin is functional, it keeps YAP and TAZ, two proteins that drive cell growth, switched off. Loss of merlin means YAP and TAZ run unchecked, promoting proliferation in schwannoma cells. SMARCB1, as a SWI/SNF chromatin remodeling subunit, also intersects the Hippo pathway — SWI/SNF and Hippo signaling crosstalk at multiple points, meaning YAP/TAZ dysregulation is not exclusive to merlin loss.
Verteporfin, already FDA-approved for treating age-related macular degeneration, has been identified as a YAP inhibitor (Liu-Chittenden Y et al., Genes Dev, 2012) and tested in schwannoma cell lines and mouse models. Because it already has an established human safety profile, verteporfin is a drug repurposing candidate — the barrier to human trials is lower than for a compound built from scratch. The Hippo/YAP pathway is one of the more active areas of SWN pre-clinical research across subtypes.
FAK — Focal Adhesion Kinase
Merlin normally suppresses FAK (focal adhesion kinase), a protein that promotes cell survival and migration. When merlin is lost, FAK becomes overactive and drives schwannoma growth. FAK inhibitors — including defactinib (VS-6063) — have been studied in schwannoma cell lines and animal models. FAK dysregulation has also been documented in SMARCB1-deficient tumor contexts, making FAK inhibition a candidate target beyond NF2-SWN. It remains an active area of pre-clinical investigation across the schwannoma family.
ErbB / HER Receptors — Specific to NF2-SWN
Schwannoma cells express ErbB2 (HER2) and ErbB3 (HER3) receptors, which drive proliferation when activated. Lapatinib, approved for HER2-positive breast cancer, was studied pre-clinically in NF2-SWN models and taken into an early clinical trial at MGH. A subset of NF2-SWN patients showed hearing improvement (Karajannis MA et al., Neuro-Oncology, 2012) — an outcome specific to vestibular schwannomas, which are the hallmark of NF2-SWN. Neratinib, one of the arms in the INTUITT-NF2 trial, is also an ErbB inhibitor. This line of research is most directly applicable to NF2-SWN patients with vestibular schwannoma burden.
MEK / ERK Signaling
Loss of merlin activates the MEK/ERK signaling cascade, which promotes cell proliferation across many tumor types. MEK inhibitors — including selumetinib (approved for NF1-related plexiform neurofibromas) and trametinib — have been studied in schwannoma models. Selumetinib’s established success in NF1 has increased interest in whether MEK inhibition can translate across the schwannomatosis family. The biology is related but not identical between subtypes — results from NF2-based models will need validation in SMARCB1 and LZTR1 contexts before conclusions can be drawn for those patients.
Mechanosensitive Ion Channels (MSCs) — Including Piezo1
Mechanosensitive ion channels (MSCs) open in response to mechanical force — physical pressure or membrane deformation — rather than voltage or chemical neurotransmitters. Piezo1 is the most studied MSC in this context. For schwannomatosis patients, tumor mass pressing against nerve tissue can physically deform adjacent cells and open these channels. But the 2026 Gutierrez et al. study (Journal of Pain) demonstrated something more: schwannoma-secreted cytokines alone — without any physical tumor pressure — are sufficient to sensitize MSCs in peripheral neurons. The chemical environment created by a tumor can activate pain through MSCs even in nerve tissue that is not physically compressed. This is why pain precedes tumor detection, and why it does not correlate with tumor size.
A 2022 study (Acheta et al., Glia) provided the first comprehensive characterization of mechanosensitive ion channels in myelinating Schwann cells — the exact cell type that forms schwannoma tumors. Of all mechanosensitive channels tested, PIEZO1 showed the highest expression in Schwann cells, and PIEZO2 the second highest. They are not merely present — they are the dominant mechanosensory apparatus of the Schwann cell. Schwannoma tumors do not just compress neighboring neurons that carry Piezo channels; the tumor cells themselves are densely equipped with them.
GsMTx-4 applied directly to Schwann cell cultures reduced TAZ nuclear localization by 45% — demonstrating that GsMTx-4 has direct functional effects in the tumor cell, not only in surrounding neurons. Activating PIEZO1 with Yoda1 (a selective agonist) had the opposite effect: TAZ nuclear enrichment increased 43%. This places PIEZO1 at the upstream end of the YAP/TAZ oncogenic axis — the same Hippo pathway that merlin normally suppresses and that NF2 and SMARCB1 mutations dysregulate. PIEZO1 overactivation in schwannoma cells may therefore drive proliferation through the same downstream targets that tumor-suppressor loss unleashes. Piezo inhibition is not only a pain intervention — it may be a tumor suppression intervention operating through the same mechanosignaling pathway already identified as a primary drug target in NF2-SWN.
Separately, selective silencing of Piezo1 in Schwann cells in peripheral nerve injury models reduced mechanical hypersensitivity (Itson-Zoske et al., 2025) — confirming that Schwann cell Piezo1 contributes to pain signaling independent of the tumor-neuron interface.
A second mechanistic connection links the Piezo pathway directly to the STARFISH trial. Inflammatory cytokines — particularly IL-6 — upregulate Piezo2 in nerve injury models. Piezo2 is the channel specifically required for tactile allodynia (pain from light touch). GsMTx-4 reversed allodynia in a trigeminal neuropathic pain model in which IL-6 and Piezo2 were both upregulated (Liu et al., 2021; Wan et al., 2024). Siltuximab, the anti-IL-6 antibody in STARFISH arm one, may therefore reduce allodynia through this same pathway: less IL-6 → less Piezo2 upregulation → lower allodynic threshold. This is a testable mechanistic hypothesis that the STARFISH data may confirm or rule out.
GsMTx-4 (described in the spider venom section of the Knowledge Bank) blocks both Piezo1 and Piezo2 by changing local membrane curvature — confirmed in multiple models. The next-generation synthetic candidate, Dooku1, was designed using the allosteric binding pocket that Yoda1 — a selective Piezo1 agonist — occupies. By understanding precisely how Yoda1 activates Piezo1 (Botello-Smith et al., Nature Communications, 2019), researchers designed a molecule that binds the same pocket but blocks the channel instead of opening it. Dooku1 is a fully synthetic small molecule — manufacturable, optimizable, and patentable. The scientific foundation exists. The pre-clinical pipeline needs sustained funding to cross the bridge to human trials.
Voltage-Gated Sodium Channels and Pain
Separate from the Piezo/mechanosensitive track, multiple groups are investigating voltage-gated sodium channel subtypes in SWN pain. Nav1.7, Nav1.8, and Nav1.9 are implicated in peripheral sensitization — the phenomenon where nerves become chronically over-reactive to stimuli in response to chemical and electrical signals. This is a distinct mechanism from Piezo-mediated pressure and cytokine-driven pain, and the two tracks are not competing — they are parallel strategies targeting different aspects of the same clinical problem: schwannomatosis pain that does not respond to standard management.
Pipeline Sources
Gutierrez C et al. Journal of Pain. 2026 (GsMTx-4, cytokine/MSC mechanism); Acheta J et al. Glia. 2022 (Piezo1/2 expression in myelinating Schwann cells); Liu-Chittenden Y et al. Genes Dev. 2012 (verteporfin as YAP inhibitor); Karajannis MA et al. Neuro-Oncology. 2012 (lapatinib NF2-SWN trial, hearing outcomes); Botello-Smith WM et al. Nature Communications. 2019 (Dooku1/Yoda1 Piezo1 binding pocket); Itson-Zoske B et al. 2025 (Piezo1 in Schwann cells and mechanical hypersensitivity); Liu B et al. 2021; Wan J et al. 2024 (IL-6 / Piezo2 / allodynia connection).