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Current therapy for glioblastoma multiforme is insufficient, with nearly universal recurrence. Available drug therapies are unsuccessful because they fail to penetrate through the region of the brain containing tumor cells and they fail to kill the cells most responsible for tumor development and therapy resistance, brain cancer stem cells (BCSCs). To address these challenges, we combined two major advances in technology: (i) brain-penetrating polymeric nanoparticles that can be loaded with drugs and are optimized for intracranial convection-enhanced delivery and (ii) repurposed compounds, previously used in Food and Drug Administration-approved products, which were identified through library screening to target BCSCs. Using fluorescence imaging and positron emission tomography, we demonstrate that brain-penetrating nanoparticles can be delivered to large intracranial volumes in both rats and pigs. We identified several agents (from Food and Drug Administration-approved products) that potently inhibit proliferation and self-renewal of BCSCs. When loaded into brain-penetrating nanoparticles and administered by convection-enhanced delivery, one of these agents, dithiazanine iodide, significantly increased survival in rats bearing BCSC-derived xenografts. This unique approach to controlled delivery in the brain should have a significant impact on treatment of glioblastoma multiforme and suggests previously undescribed routes for drug and gene delivery to treat other diseases of the central nervous system.

Many synthetic polycationic vectors for non-viral gene delivery show high efficiency in vitro , but their usually excessive charge density makes them toxic for in vivo applications. Here we describe the synthesis of a series of high molecular weight terpolymers with low charge density, and show that they exhibit efficient gene delivery, some surpassing the efficiency of the commercial transfection reagents Polyethylenimine and Lipofectamine 2000. The terpolymers were synthesized via enzyme-catalyzed copolymerization of lactone with dialkyl diester and amino diol, and their hydrophobicity adjusted by varying the lactone content and by selecting a lactone comonomer of specific ring size. Targeted delivery of the pro-apoptotic TRAIL gene to tumour xenografts by one of the terpolymers results in significant inhibition of tumour growth, with minimal toxicity both in vitro and in vivo . Our findings suggest that the gene delivery ability of the terpolymers stems from their high molecular weight and increased hydrophobicity, which compensates for their low charge density. Many synthetic polymer nanoparticles used for non-viral gene delivery contain excess cations on their surface, which makes the particles cytotoxic and the delivery of genes inefficient. Terpolymers with a low charge density, high molecular weight and increased hydrophobicity are now shown to have minimal toxicity, and to efficiently deliver the apoptosis-inducing TRAIL gene to transplanted tumours in mice.

Murat Günel and colleagues identify recurrent mutations in POLR2A , which encodes the catalytic subunit of RNA polymerase II, in a subset of meningiomas. They find that POLR2A -mutant tumors can be distinguished on the basis of their super-enhancer and gene expression profiles, which show dysregulation of key meningeal identity genes. RNA polymerase II mediates the transcription of all protein-coding genes in eukaryotic cells, a process that is fundamental to life. Genomic mutations altering this enzyme have not previously been linked to any pathology in humans, which is a testament to its indispensable role in cell biology. On the basis of a combination of next-generation genomic analyses of 775 meningiomas, we report that recurrent somatic p.Gln403Lys or p.Leu438_His439del mutations in POLR2A , which encodes the catalytic subunit of RNA polymerase II (ref. 1 ), hijack this essential enzyme and drive neoplasia. POLR2A mutant tumors show dysregulation of key meningeal identity genes 2 , 3 , including WNT6 and ZIC1 / ZIC4 . In addition to mutations in POLR2A , NF2 , SMARCB1, TRAF7 , KLF4 , AKT1 , PIK3CA , and SMO 4 , 5 , 6 , 7 , 8 , we also report somatic mutations in AKT3 , PIK3R1 , PRKAR1A , and SUFU in meningiomas. Our results identify a role for essential transcriptional machinery in driving tumorigenesis and define mutually exclusive meningioma subgroups with distinct clinical and pathological features.

A subset of patients with malignant glioma comes to medical attention before their masses show rim enhancement and central necrosis. Tumors in those cases are frequently located in eloquent areas of the brain. Tissue diagnosis is limited to stereotactic biopsy providing limited material for accurate grading. We conducted this study to determine whether imaging characteristics of early stages of malignant gliomas could aid in timely definitive diagnosis. We retrospectively analyzed patients with newly diagnosed malignant glioma seen at the Yale Brain Tumor Center between 2002 and 2005. Patients with typical radiographic presentation were excluded. Of 89 patients, eight meeting the inclusion criteria were identified. In five patients, patchy or small nodular enhancing lesions without central necrosis were present within the tumor mass. Diffusion-weighted imaging (DWI) showed areas of increased signal intensity in all cases. Apparent diffusion coefficient maps (ADC) revealed low-signal intensity in corresponding areas. At the time of imaging, biopsy was performed in seven patients but diagnosis of malignant glioma could only be established prior to further tumor growth in four cases. The diagnosis in the early stages of malignant glioma can be challenging in a subset of cases. Information obtained through DWI should be incorporated in the clinical decision-making process. Mass lesions displaying decreased water diffusion indicating high cellularity, are suggestive of a high-grade glioma. Biopsies are recommended. However, even when biopsies are inconclusive, a strong suspicion of malignant glioma should be considered.

Current therapy for glioblastoma multiforme (GBM) is largely ineffective, with nearly universal tumor recurrence. The failure of current therapy is primarily due to the lack of approaches for the efficient delivery of therapeutics to diffuse tumors in the brain. In our prior study, we developed brain-penetrating nanoparticles that are capable of penetrating brain tissue and distribute over clinically relevant volumes when administered via convection-enhanced delivery (CED). We demonstrated that these particles are capable of efficient delivery of chemotherapeutics to diffuse tumors in the brain, indicating that they may serve as a groundbreaking approach for the treatment of GBM. In the original study, nanoparticles in the brain were imaged using positron emission tomography (PET). However, clinical translation of this delivery platform can be enabled by engineering a non-invasive detection modality using magnetic resonance imaging (MRI). For this purpose, we developed chemistry to incorporate superparamagnetic iron oxide (SPIO) into the brain-penetrating nanoparticles. We demonstrated that SPIO-loaded nanoparticles, which retain the same morphology as nanoparticles without SPIO, have an excellent transverse (T 2 ) relaxivity. After CED, the distribution of nanoparticles in the brain (i.e., in the vicinity of injection site) can be detected using MRI and the long-lasting signal attenuation of SPIO-loaded brain-penetrating nanoparticles lasted over a one-month timecourse. Development of these nanoparticles is significant as, in future clinical applications, co-administration of SPIO-loaded nanoparticles will allow for intraoperative monitoring of particle distribution in the brain to ensure drug-loaded nanoparticles reach tumors as well as for monitoring the therapeutic benefit with time and to evaluate tumor relapse patterns.

Over the past two decades, the accumulated clinical and research experience has improved our understanding the biology of WHO grade II gliomas (G2G). While there have been relatively few randomized clinical trials in this population, those that exist and the experience from clinical reports have enhanced our understanding of how these tumors progressively increase in size, accumulate additional genetic mutations and ultimately transform into high-grade lesions. Our ability to reliably predict the time sequence of this transformation remains a challenge; however, recent findings have started to clarify selection criteria for adjuvant treatment. G2G remain a fatal disease for many patients. Continued investigation into the biology of these lesions will likely provide the information needed to select more appropriate therapy based on biological and genetic differences in these unique lesions. Some of this information will be derived from the study of high-grade lesions. However, experience has shown that much of the work on high-grade lesions is also applicable to low-grade lesions.

The management of patients with intracerebral glioma is focused upon the selection of treatment modalities that prolong survival while minimizing the risk of complications and maintaining an adequate quality of life. In the author's experience, patients with low-grade gliomas are best treated with gross total resection in order to decrease the risk of recurrence with higher grade lesions. In patients with high-grade glioma, age, Karnofsky Performance Status, histology and the use of radiotherapy are major predictors of survival. The extent of surgical resection is less important than these factors, but recent series support a survival advantage in patients that undergo more extensive surgery. The major complication from surgical resection is neurologic impairment. Careful preoperative planning with the assistance of functional MRI and intraoperative mapping is useful for accomplishing the maximum safe resection.

Despite advances in diagnostic imaging and drug discovery, primary malignant brain tumors remain fatal. Median survival for patients with the most severe forms is rarely past eight months. The severity of the disease and the lack of substantial improvement in patient survival demand that new approaches be explored in drug delivery to brain tumors. Recently, local delivery of chemotherapy to brain tumors has provided a way to circumvent the blood-brain barrier, allowing delivery of chemotherapy drugs directly to malignant cells in the brain. Two methods of local delivery have been developed: polymeric-controlled release and convection-enhanced delivery. Controlled release utilizes degradable or non-degradable polymers as carriers of chemotherapy; polymer implants or microparticles are implanted locally to introduce a sustained source of drug for periods of days or months. Convection-enhanced delivery employs the bulk flow of drugs dissolved in fluid, which is introduced intracranially using a catheter and pump. The convective fluid flow is capable of delivering drugs great distances within the brain, potentially treating invasive cells at a distance from the catheter infusion site. These two new delivery strategies are capable of delivering both standard chemotherapeutic drugs and new methods of anti-cancer therapy. Taken individually, or used in tandem, they represent a potential revolution in brain cancer treatment.

We report genomic analysis of 300 meningiomas, the most common primary brain tumors, leading to the discovery of mutations in TRAF7, a proapoptotic E3 ubiquitin ligase, in nearly one-fourth of all meningiomas. Mutations in TRAF7 commonly occurred with a recurrent mutation (K409Q) in KLF4, a transcription factor known for its role in inducing pluripotency, or with AKT1 E17K , a mutation known to activate the PI3K pathway. SMO mutations, which activate Hedgehog signaling, were identified in ∼5% of non-NF2 mutant meningiomas. These non-NF2 meningiomas were clinically distinctive—nearly always benign, with chromosomal stability, and originating from the medial skull base. In contrast, meningiomas with mutant NF2 and/or chromosome 22 loss were more likely to be atypical, showing genomic instability, and localizing to the cerebral and cerebellar hemispheres. Collectively, these findings identify distinct meningioma subtypes, suggesting avenues for targeted therapeutics.