Local Delivery of Chemotherapy to Aggressive Meningiomas using a Bioresorbable Implant

Meningiomas are tumors that grow from the membranes covering the central nervous system, including the brain and spinal cord. They are the most common type of tumor arising in the adult CNS, with over 36,000 diagnosed every year in the United States. Treatment of meningiomas has remained unchanged for decades, including maximal safe resection with adjuvant radiotherapy (RT) in aggressive cases. Approximately 30% of tumors recur within five years, causing substantial morbidity. Many patients ultimately die from disease. Such recurrences are due to anatomically constrained sub-total surgical resection or residual microscopic disease left behind after gross total resection. Despite extensive investigation, there are no effective chemotherapies for meningiomas, due in part to dosing limitations that arise from systemic toxicity. Local delivery of chemotherapeutics could circumvent the failures of previous clinical trials, and provide durable remission in meningiomas that cannot be managed with further surgery or radiation. A similar approach already exists for diffusely infiltrative gliomas using Gliadel® wafers, but such wafers are not curative in infiltrative gliomas because the tumor cells can migrate through the brain, away from the wafers. In contrast, meningioma cells cannot migrate in this fashion, and only rarely metastasize. Thus, meningiomas may be more vulnerable to localized chemotherapy approaches than infiltrative gliomas. Based on a high-throughput screen of existing anticancer compounds against our library of patient-derived meningiomas, we identified three drugs—docetaxel, bortezomib, and romidepsin (DBR)—as being the most cytotoxic chemotherapies against the broadest molecular subtypes of meningiomas. While systemic delivery of these drugs was highly toxic in mice, local delivery of this DBR cocktail via direct intratumoral injection was active against two in vivo models of human meningioma, with no notable side effects. We then found that polyanhydride wafers containing DBR chemotherapy also block meningioma growth, again without notable side effects. Therefore, our central hypothesis is that bioresorbable wafers containing a cocktail of chemotherapies are a safe and effective treatment for aggressive meningiomas. In Aim 1 we will develop wafers containing all three drugs to form DBR triple therapy wafers. In Subaim 1a we will test the wafers in two contexts—one where a formed tumor is already present, and one in which only microscopic cells are present. In Subaim 1b, we will create a version of the wafers with an outer drug-free shell to delay drug release, so as to allow for local postsurgical wound healing in patients before chemotherapy release. Aim 2 focuses on larger animals, with Subaim 2a exploring the pharmacokinetics of DBR wafers in minipigs, and Subaim 2b as a single- arm trial in canine meningioma patients. Molecular analysis of canine tumors is included within Subaim 2c. Both Aims include detailed tissue-based toxicologic studies to establish DBR wafer safety. This is the first time such an approach has been tried against meningiomas. Success in this project will therefore advance a novel therapeutic strategy against a common and challenging CNS tumor. Project Number: 1R01CA305145-01A1 | Fiscal Year: 2026 | NIH Institute/Center: National Cancer Institute (NCI) | Principal Investigator: Craig Horbinski | Institution: MAYO CLINIC JACKSONVILLE, JACKSONVILLE, FL | Award Amount: $620,671 | Activity Code: R01 | Study Section: Advancing Therapeutics A Study Section [ATA] View on NIH RePORTER: https://reporter.nih.gov/project-details/11379615