DDEL-12. LOCAL DELIVERY OF CHEMOTHERAPIES VIA BIORESORBABLE IMPLANT IN MENINGIOMAS

Abstract Many meningiomas recur despite repeated surgical resections and radiation, and patients must undergo progressively morbid surgical procedures due to recurrent or progressive disease. However, unlike most gliomas, meningiomas do not diffusely infiltrate throughout the brain on a single-cell basis, but instead recur and invade locally. Thus, they may be particularly vulnerable to localized chemotherapy. To investigate this, we screened 13 patient-derived primary meningioma cell cultures and two commercially available meningioma cell lines using a library of 147 FDA-approved compounds. We identified drugs with elevated potency across all meningiomas, including bortezomib (mean IC50 = 7nM) and romidepsin (mean IC50 = 18nM), as well as drugs with selective potency against specific samples, such as docetaxel (IC50 range 6nM to >10uM). We reasoned that delivery of a multi-drug cocktail with independent anti-neoplastic mechanisms would provide the strongest therapeutic effect in meningiomas. As systemic treatment with combination agents resulted in severe toxicity in mice, we performed local injection of bortezomib / romidepsin / docetaxel (BRD) triple therapy over 24 days in flank xenografts of IOMM-LEE and CH157 meningiomas. Tumor growth was reduced by 71-88% relative to vehicle (p<0.01), and mice showed no systemic toxicity with local therapy. Notably, the addition of radiotherapy did not further enhance the effect of BRD. To optimize local delivery, we developed a polyanhydride bioresorbable wafer designed to fit in a meningioma resection cavity, analogous to carmustine wafers used in gliomas. Intracranial implantation of wafers caused no local toxicity or inflammation in mice. Docetaxel-loaded wafers prevented the growth of flank-injected IOMM-LEE cells relative to wafers without drug (0 mm3 vs. 230 mm3 at 3 weeks post-injection, N=5/group, p<0.01). Our results demonstrate that bioresorbable wafers containing a cocktail of potent chemotherapies may be an effective new strategy against locally aggressive meningiomas.