The Children’s Tumor Foundation is pleased to announce a significant investment of more than $995,000 in Drug Discovery Initiative (DDI) Awards focused on drug discovery for the most challenging manifestations of neurofibromatosis type 1 (NF1), pain in schwannomatosis (SWN), and vestibular schwannomas in patients with NF2-related schwannomatosis (NF2-SWN).
Ljubica Caldovic, PhD
Children’s Research Institute (CNMC)
Targeting PRMT5 in MTAP-Deleted NF1 High Grade Gliomas
Neurofibromatosis Type 1 (NF1) is a genetic disorder characterized by mutations in the NF1 gene. These mutations result in overactivation of the Ras/MAPK signaling pathway, promoting unchecked tumor cell growth and survival. Low-grade gliomas (LGGs) commonly develop in children with NF1, with some progressing to high-grade gliomas (HGGs) during late adolescence or early adulthood. NF1 HGG patients generally have poor overall survival, underscoring the need for improved therapeutic strategies. One of the most frequent genetic mutations in NF1 HGGs (57%) occurs in the CDKN2A/B gene, often (90%) co-occurring with a mutation in the MTAP gene. MTAP encodes methylthioadenosine phosphorylase (MTAP), crucial for the methionine salvage pathway. Loss of MTAP function leads to methylthioadenosine (MTA) accumulation, creating a vulnerability in protein methyltransferase 5 (PRMT5).
Previous studies have demonstrated the effectiveness of PRMT5 inhibitors in inducing tumor cell death in cancers with MTAP deletions. However, little research has been conducted on the efficacy of these inhibitors in NF1 HGGs with MTAP deletions, nor on how current medications for NF1 HGGs will interact with PRMT5 inhibitors. As a preliminary investigation, PRMT5 inhibitors were tested independently and in combination with MEK inhibitors on NF1-mutant cells with and without MTAP deletion. The results indicated that MTAP-deleted cells were more sensitive to PRMT5 inhibitors than cells with intact MTAP. Moreover, PRMT5 inhibitors demonstrated strong efficacy when combined with MEK inhibitors in these cells.
To further validate these findings, this project aims to test PRMT5 inhibitors on NF1 glioma cell lines and examine their mechanisms in inhibiting tumor growth. Gene and protein expression analyses will elucidate the effects of PRMT5 inhibition on NF1 HGGs. Additionally, the project seeks to explore the efficacy of PRMT5 and MEK inhibitor combinations in both cell cultures and mouse models. The results of this study will substantiate PRMT5 as a therapeutic target for MTAP-deleted NF1 gliomas and provide novel drug combinations to improve survival outcomes for NF1 patients. This research holds significant promise for identifying new targeted therapies for NF1 HGG patients, advancing the field of translational medicine.
Kimberly Ostrow, PhD
Johns Hopkins University School of Medicine
GsMTtx-4 as a Novel Inhibitor to Block Non-NF2-SWN Pain
Schwannomatosis (SWN) patients often develop multiple tumors along the major nerves, leading to severe pain. Although surgical resection is the current standard of care for painful schwannomas, the sheer number of tumors often makes surgery impractical. Medication-based treatment of SWN-related pain remains largely a trial-and-error process, highlighting the urgent need for alternative pain therapies. The reclassification of SWN into subgroups based on LZTR1 or SMARCB1 mutations has introduced additional challenges. This project aims to identify a common pathway that can be targeted in all SWN patients.
It is hypothesized that schwannomas, by growing along the nerves, activate ion channels involved in detecting touch, pressure, and stretching. These channels open in response to mechanical stress, triggering a cascade of factors that lead to pain. Years of postdoctoral research in this lab resulted in the isolation of a small protein, GsMTx-4, from the venom of the Chilean Rose tarantula. This venom, while harmless to humans, contains components with potential therapeutic applications. GsMTx-4 was found to block pressure-sensing ion channels, preventing their activation.
This project proposes to decrease SWN-related pain by blocking these ion channels using GsMTx-4. Previous experiments demonstrated that injecting tumor-secreted products from painful schwannomas into a healthy mouse’s footpad heightened the mouse’s sensitivity to light touch. The next step is to test whether GsMTx-4 can block this sensitivity. Other research has shown GsMTx-4’s potential to treat conditions such as muscular dystrophy and cardiac arrhythmias, with promising results. It is non-toxic in mice, and pharmaceutical companies are exploring its use as a therapy for muscular dystrophy.
This proposal represents the first attempt to use a direct blocker of pressure-sensitive ion channels to treat tumor-related pain. If successful, the study will represent a significant breakthrough in SWN research. Collaboration with colleagues developing mouse models of SWN will further assess GsMTx-4’s therapeutic potential, with the ultimate goal of advancing the drug into clinical trials for treating painful tumors in SWN patients.
Daochun Sun, PhD
The Medical College of Wisconsin
Repurposing Montelukast to Treat Plexiform Neurofibromas in Combination with Selumetinib
Selumetinib is currently the only FDA-approved targeted therapy for pediatric plexiform neurofibromas (PN). This project seeks to accelerate research by repurposing other FDA-approved drugs to treat PN, significantly speeding up the clinical evaluation process. The existing safety and dosage profiles of these drugs can reduce risks and increase success rates in new clinical trials for PN. A data analysis pipeline has been developed to prioritize drug candidates from PN cell line-based drug screening data using computational methods and NIH database searches. Among the top candidates are cysteinyl leukotriene receptor antagonists, including Montelukast, Zafirlukast, and Pranlukast, which demonstrate inhibitory effects on PN cells.
Preliminary data show that combining Montelukast with selumetinib can significantly lower the required dose of selumetinib to inhibit PN cell growth compared to using selumetinib alone. The success of this research could lead to a novel therapeutic strategy that reduces these adverse effects by combining two FDA-approved drugs.
Montelukast, approved by the FDA in 1998 as an anti-asthma drug, influences immune system cells, particularly macrophages, which are abundant in the NF1 tumor microenvironment. The M2 macrophage phenotype has been reported to promote tumor growth, and preliminary data suggest that Montelukast may inhibit M2 macrophage viability. This could represent an additional mechanism to improve PN prognosis.
The study will utilize PN cell lines, mouse bone marrow-derived macrophages, and tumor-bearing mice to evaluate the effects of Montelukast and its combination with selumetinib. The focus will be on assessing PN cell growth, macrophage viability and phenotype, and tumor growth/regrowth in mouse models post-surgery. This investigation could provide critical insights into reducing the adverse effects of selumetinib and enhancing therapeutic outcomes for patients with PN.
Keila Torres, PhD
University of Texas M.D. Anderson Cancer Center
In Vivo Assessment of BET Blockade Combined with PARP Inhibition to Sensitize MPNST to Radiation Therapy
Individuals with neurofibromatosis type 1 (NF1) face a 10-15% risk of developing malignant peripheral nerve sheath tumors (MPNSTs). These aggressive tumors are a significant cause of morbidity and mortality, with a five-year survival rate of only 35-60%. MPNSTs are resistant to chemotherapy and radiation therapy, often recur, and are generally fatal. Surgical removal is the only potentially curative treatment, yet this is often impossible due to the tumor’s location or metastatic spread. Thus, there is a pressing need for novel and effective therapies for MPNSTs.
This project seeks to exploit known epigenetic dysregulations and DNA damage repair vulnerabilities in MPNSTs. Bromodomain and extra-terminal motif (BET) inhibition (BETi) has been shown to slow MPNST growth, and preliminary data indicate that BET inhibitors reduce the expression of DNA damage repair genes. Furthermore, poly(ADP) ribose polymerase inhibitors (PARPi), which interfere with DNA damage signaling, have shown promise in MPNST treatment. While both BETi and PARPi slow tumor progression, neither approach fully halts tumor growth. The hypothesis is that combining BET inhibition with PARP inhibition will sensitize MPNSTs to radiation therapy, enhancing tumor cell death by downregulating DNA damage repair gene expression.
The project will assess the efficacy of the BET inhibitor ZEN-3694 on MPNST cell lines and in mouse models. Additionally, it will explore the potential of combining ZEN-3694 with the PARP inhibitor Olaparib, with or without radiation therapy, to enhance treatment outcomes in MPNST mouse models. This study aims to improve therapeutic options for NF1 patients with MPNST, offering a potential new strategy for integrating BETi and PARPi into radiation therapy regimens to enhance anti-tumor effects and improve survival outcomes.
Lei Xu, MD
Massachusetts General Hospital
Targeting HIF-2 for the Treatment of NF2-SWN Vestibular Schwannoma
Current treatments for NF2-related schwannomatosis (NF2-SWN) patients, particularly those whose tumors continue to grow despite bevacizumab treatment, remain limited. In some cases, patients must stop bevacizumab due to side effects. The FDA recently approved belzutifan, a hypoxia-inducible factor-2 alpha (HIF-2α) inhibitor, for renal cell carcinoma, offering a promising new avenue for NF2 patients. HIF-2α is involved in tumors’ adaptation to low oxygen levels, a common feature of vestibular schwannoma. This study hypothesizes that belzutifan, in combination with anti-VEGF therapy, may provide a more effective treatment than anti-VEGF therapy alone.
The project will use a mouse model that simulates tumor-induced hearing loss to evaluate whether belzutifan can slow tumor growth and prevent hearing loss. The efficacy of belzutifan will be compared to anti-VEGF treatment, and its ability to rescue vestibular schwannomas that do not respond to anti-VEGF therapy will also be examined. Finally, the study aims to confirm the validity of HIF-2α as a therapeutic target in NF2-SWN patient tumor tissues.
This collaborative study between experts in NF2-SWN tumor biology and NF patient care could introduce a new treatment option for vestibular schwannomas that are unresponsive to current therapies. If successful, it could also suggest a new combination strategy to improve the efficacy of bevacizumab in treating NF2-SWN patients.
