Docetaxel targets aggressive methylation profiles and serves as a radiosensitizer in high-risk meningiomas.

BACKGROUND: Meningioma is the most common primary intracranial tumor in adults. A subset of these tumors recur and invade the brain, even after surgery and radiation, resulting in significant disability. There is currently no standard-of-care chemotherapy for meningiomas. As genomic DNA methylation profiling can prognostically stratify these lesions, we sought to determine whether any existing chemotherapies might be effective against meningiomas with high-risk methylation profiles. METHODS: A previously published dataset of meningioma methylation profiles was used to screen for clinically significant CpG methylation events and associated cellular pathways. Based on these results, patient-derived meningioma cell lines were used to test candidate drugs in vitro and in vivo, including efficacy in conjunction with radiotherapy. RESULTS: We identified 981 genes for which methylation of mapped CpG sites was related to progression-free survival in meningiomas. Associated molecular pathways were cross-referenced with FDA-approved cancer drugs, which nominated Docetaxel as a promising candidate for further preclinical analyses. Docetaxel arrested growth in 17 meningioma cell sources, representing all tumor grades, with a clinically favorable IC50 values ranging from 0.3 nM to 10.7 mM. The inhibitory effects of this medication scaled with tumor doubling time, with maximal benefit in fast-growing lesions. The combination of Docetaxel and radiation therapy increased markers of apoptosis and double-stranded DNA breaks, and extended the survival of mice engrafted with meningioma cells relative to either modality alone. CONCLUSIONS: Global patterns of DNA methylation may be informative for the selection of chemotherapies against meningiomas, and existing drugs may enhance radiation sensitivity in high-risk cases.

Modeling Therapy-Driven Evolution of Glioblastoma with Patient-Derived Xenografts.

Adult-type diffusely infiltrating gliomas, of which glioblastoma is the most common and aggressive, almost always recur after treatment and are fatal. Improved understanding of therapy-driven tumor evolution and acquired therapy resistance in gliomas is essential for improving patient outcomes, yet the majority of the models currently used in preclinical research are of therapy-naïve tumors. Here, we describe the development of therapy-resistant IDH-wildtype glioblastoma patient-derived xenografts (PDX) through orthotopic engraftment of therapy naïve PDX in athymic nude mice, and repeated in vivo exposure to the therapeutic modalities most often used in treating glioblastoma patients: radiotherapy and temozolomide chemotherapy. Post-temozolomide PDX became enriched for C>T transition mutations, acquired inactivating mutations in DNA mismatch repair genes (especially MSH6), and developed hypermutation. Such post-temozolomide PDX were resistant to additional temozolomide (median survival decrease from 80 days in parental PDX to 42 days in a temozolomide-resistant derivative). However, temozolomide-resistant PDX were sensitive to lomustine (also known as CCNU), a nitrosourea which induces tumor cell apoptosis by a different mechanism than temozolomide. These PDX models mimic changes observed in recurrent GBM in patients, including critical features of therapy-driven tumor evolution. These models can therefore serve as valuable tools for improving our understanding and treatment of recurrent glioma.

SLFN11 negatively regulates non-canonical NFkB signaling to promote glioblastoma progression.

Glioblastoma (GBM) is an aggressive and incurable brain tumor in nearly all instances, whose disease progression is driven in part by the glioma stem cell (GSC) subpopulation. Here, we explored the effects of Schlafen family member 11 (SLFN11) in the molecular, cellular and tumor biology of GBM. CRISPR/Cas9 mediated knockout (KO) of SLFN11 inhibited GBM cell proliferation and neurosphere growth and was associated with reduced expression of progenitor/stem cell marker genes, such as NES, SOX2 and CD44. Loss of SLFN11 stimulated expression of NF-κB target genes, consistent with a negative regulatory role for SLFN11 on the NF-κB pathway. Further, our studies identify p21 as a direct transcriptional target of NF-κB2 in GBM whose expression was stimulated by loss of SLFN11. Genetic disruption of SLFN11 blocked GBM growth and significantly extended survival in an orthotopic patient-derived xenograft model. Together, our results identify SLFN11 as a novel component of signaling pathways that contribute to GBM and GSC with implications for future diagnostic and therapeutic strategies.

Ultrasound-mediated Delivery of Paclitaxel for Glioma: A Comparative Study of Distribution, Toxicity, and Efficacy of Albumin-bound Versus Cremophor Formulations.

PURPOSE: Paclitaxel shows little benefit in the treatment of glioma due to poor penetration across the blood-brain barrier (BBB). Low-intensity pulsed ultrasound (LIPU) with microbubble injection transiently disrupts the BBB allowing for improved drug delivery to the brain. We investigated the distribution, toxicity, and efficacy of LIPU delivery of two different formulations of paclitaxel, albumin-bound paclitaxel (ABX) and paclitaxel dissolved in cremophor (CrEL-PTX), in preclinical glioma models. EXPERIMENTAL DESIGN: The efficacy and biodistribution of ABX and CrEL-PTX were compared with and without LIPU delivery. Antiglioma activity was evaluated in nude mice bearing intracranial patient-derived glioma xenografts (PDX). Paclitaxel biodistribution was determined in sonicated and nonsonicated nude mice. Sonications were performed using a 1 MHz LIPU device (SonoCloud), and fluorescein was used to confirm and map BBB disruption. Toxicity of LIPU-delivered paclitaxel was assessed through clinical and histologic examination of treated mice. RESULTS: Despite similar antiglioma activity in vitro, ABX extended survival over CrEL-PTX and untreated control mice with orthotropic PDX. Ultrasound-mediated BBB disruption enhanced paclitaxel brain concentration by 3- to 5-fold for both formulations and further augmented the therapeutic benefit of ABX. Repeated courses of LIPU-delivered CrEL-PTX and CrEL alone were lethal in 42% and 37.5% of mice, respectively, whereas similar delivery of ABX at an equivalent dose was well tolerated. CONCLUSIONS: Ultrasound delivery of paclitaxel across the BBB is a feasible and effective treatment for glioma. ABX is the preferred formulation for further investigation in the clinical setting due to its superior brain penetration and tolerability compared with CrEL-PTX.