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Weijun Wang, Steve Swenson, Hee-Yeon Cho, Florence M. Hofman, Axel H. Schönthal and Thomas C. Chen

OBJECTIVE

Many pharmaceutical agents are highly potent but are unable to exert therapeutic activity against disorders of the central nervous system (CNS), because the blood-brain barrier (BBB) impedes their brain entry. One such agent is bortezomib (BZM), a proteasome inhibitor that is approved for the treatment of multiple myeloma. Preclinical studies established that BZM can be effective against glioblastoma (GBM), but only when the drug is delivered via catheter directly into the brain lesion, not after intravenous systemic delivery. The authors therefore explored alternative options of BZM delivery to the brain that would avoid invasive procedures and minimize systemic exposure.

METHODS

Using mouse and rat GBM models, the authors applied intranasal drug delivery, where they co-administered BZM together with NEO100, a highly purified, GMP-manufactured version of perillyl alcohol that is used in clinical trials for intranasal therapy of GBM patients.

RESULTS

The authors found that intranasal delivery of BZM combined with NEO100 significantly prolonged survival of tumor-bearing animals over those that received vehicle alone and also over those that received BZM alone or NEO100 alone. Moreover, BZM concentrations in the brain were higher after intranasal co-delivery with NEO100 as compared to delivery in the absence of NEO100.

CONCLUSIONS

This study demonstrates that intranasal delivery with a NEO100-based formulation enables noninvasive, therapeutically effective brain delivery of a pharmaceutical agent that otherwise does not efficiently cross the BBB.

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Weijun Wang, Hee-Yeon Cho, Rachel Rosenstein-Sisson, Nagore I. Marín Ramos, Ryan Price, Kyle Hurth, Axel H. Schönthal, Florence M. Hofman and Thomas C. Chen

OBJECTIVE

Glioblastoma (GBM) is the most prevalent and the most aggressive of primary brain tumors. There is currently no effective treatment for this tumor. The proteasome inhibitor bortezomib is effective for a variety of tumors, but not for GBM. The authors' goal was to demonstrate that bortezomib can be effective in the orthotopic GBM murine model if the appropriate method of drug delivery is used. In this study the Alzet mini-osmotic pump was used to bring the drug directly to the tumor in the brain, circumventing the blood-brain barrier; thus making bortezomib an effective treatment for GBM.

METHODS

The 2 human glioma cell lines, U87 and U251, were labeled with luciferase and used in the subcutaneous and intracranial in vivo tumor models. Glioma cells were implanted subcutaneously into the right flank, or intracranially into the frontal cortex of athymic nude mice. Mice bearing intracranial glioma tumors were implanted with an Alzet mini-osmotic pump containing different doses of bortezomib. The Alzet pumps were introduced directly into the tumor bed in the brain. Survival was documented for mice with intracranial tumors.

RESULTS

Glioma cells were sensitive to bortezomib at nanomolar quantities in vitro. In the subcutaneous in vivo xenograft tumor model, bortezomib given intravenously was effective in reducing tumor progression. However, in the intracranial glioma model, bortezomib given systemically did not affect survival. By sharp contrast, animals treated with bortezomib intracranially at the tumor site exhibited significantly increased survival.

CONCLUSIONS

Bypassing the blood-brain barrier by using the osmotic pump resulted in an increase in the efficacy of bortezomib for the treatment of intracranial tumors. Thus, the intratumoral administration of bortezomib into the cranial cavity is an effective approach for glioma therapy.

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Anthony D'Oro, Mark J. Spoonamore, Jeremiah R. Cohen, Frank L. Acosta, Patrick C. Hsieh, John C. Liu, Thomas C. Chen, Zorica Buser and Jeffrey C. Wang

OBJECT

The objective of this study was to compare the incidence of degeneration and need for subsequent fusion surgery between patients who were treated nonsurgically and patients treated with fusion after a diagnosis of thoracic-or lumbar-level fracture without degenerative disease.

METHODS

The authors performed a retrospective study of Orthopedic United Healthcare patients diagnosed with thoracic or lumbar fracture. Patients were filtered into thoracic and lumbar fracture groups using diagnostic codes and then assigned to one of 2 treatment subgroups (fusion surgery or no surgery) on the basis of procedural codes. Disc degeneration and follow-up surgery were recorded. Chi-square statistical analysis was used.

RESULTS

Of 3699 patients diagnosed with a thoracic fracture, 117 (3.2%) underwent thoracic fusion and 3215 (86.9%) were treated nonsurgically. Within 3 years, 147 (4.6%) patients from the nonsurgical subgroup and fewer than 11 (0.9%–8.5%) from the fusion subgroup were diagnosed with thoracic disc degeneration. From the nonsurgical subgroup, 11 (0.3%) patients underwent a thoracic surgery related to disc degeneration compared with zero from the fusion group (p > 0.05). Of 5016 patients diagnosed with lumbar fracture, 150 (3.0%) underwent fusion and 4371 (87.1%) had no surgery. Within 3 years, 503 patients (11.5%) from the nonsurgical subgroup and 35 (23.3%) from the fusion subgroup were diagnosed with lumbar disc degeneration (p < 0.05). From the nonsurgical subgroup, 42 (1.0%) went on to have surgery related to disc degeneration, compared with fewer than 11 (0.7%–6.7%) from the fusion subgroup (values not precise due to privacy limitations).

CONCLUSIONS

Fusion surgery for thoracic fracture does not appear to increase the likelihood of undergoing future surgery. In the lumbar region, initial fusion surgery appears to increase the incidence of disc degeneration and could potentially necessitate future surgeries.

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Thomas C. Chen, Gina R. Napolitano, Frank Adell, Axel H. Schönthal and Yehoshua Shachar

Patients with leptomeningeal carcinomatosis face a particularly grim prognosis. Current treatment consists of intrathecal delivery of methotrexate (MTX) or cytosine arabinoside (Ara-C) via Ommaya reservoir or lumbar puncture. Yet despite these interventions, the median survival after diagnosis is only 4–7 months. To address inherent shortcomings of current treatments and provide a more effective therapeutic approach, the Pharmaco-Kinesis Corporation has developed a novel type of implantable pump capable of delivering intrathecal chemotherapy (i.e., MTX) in a metronomic fashion with electronic feedback. The Metronomic Biofeedback Pump (MBP) consists of 3 components: 1) a 2-lumen catheter; 2) a microfluidic delivery pump with 2 reservoirs; and 3) a spectrophotometer monitoring MTX concentrations in the CSF. Using an animal model of intraventricular drug delivery, the authors demonstrate that the MBP can reliably deliver volumes of 500 μl/min, consistently measure real-time intrathecal MTX concentrations via CSF aspiration, and provide biofeedback with the possibility of instant control and delivery adjustments. Therefore, this novel approach to chemotherapy minimizes toxic drug levels and ensures continuous exposure at precisely adjusted, individualized therapeutic levels. Altogether, application of the MBP is expected to increase survival of patients with leptomeningeal carcinomatosis, and appropriate Phase I and II trials are pending.

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Weijun Wang, Walavan Sivakumar, Shering Torres, Niyati Jhaveri, Vijaya Pooja Vaikari, Alex Gong, Adam Howard, Encouse B. Golden, Stan G. Louie, Axel H. Schönthal, Florence M. Hofman and Thomas C. Chen

OBJECT

Bevacizumab (Avastin), an antibody to vascular endothelial growth factor (VEGF), alone or in combination with irinotecan (Camptosar [CPT-11]), is a promising treatment for recurrent glioblastoma. However, the intravenous (IV) administration of bevacizumab produces a number of systemic side effects, and the increase in survival it provides for patients with recurrent glioblastoma is still only a few months. Because bevacizumab is an antibody against VEGF, which is secreted into the extracellular milieu by glioma cells, the authors hypothesized that direct chronic intratumoral delivery techniques (i.e., convection-enhanced delivery [CED]) can be more effective than IV administration. To test this hypothesis, the authors compared outcomes for these routes of bevacizumab application with respect to animal survival, microvessel density (MVD), and inflammatory cell distribution.

METHODS

Two human glioma cell lines, U87 and U251, were used as sources of intracranial tumor cells. The glioma cell lines were implanted into the brains of mice in an orthotopic xenograft mouse tumor model. After 7 days, the mice were treated with one of the following: 1) vehicle, 2) CED bevacizumab, 3) IV bevacizumab, 4) intraperitoneal (IP) irinotecan, 5) CED bevacizumab plus IP irinotecan, or 6) IV bevacizumab plus IP irinotecan. Alzet micro-osmotic pumps were used to introduce bevacizumab directly into the tumor. Survival was monitored. Excised tumor tissue samples were immunostained to measure MVD and inflammatory cell and growth factor levels.

RESULTS

The results demonstrate that mice treated with CED of bevacizumab alone or in combination with irinotecan survived longer than those treated systemically; CED-treated animals survived 30% longer than IV-treated animals. In combination studies, CED bevacizumab plus CPT-11 increased survival by more than 90%, whereas IV bevacizumab plus CPT-11 increased survival by 40%. Furthermore, CED bevacizumab-treated tissues exhibited decreased MVD compared with that of IV-treated tissues. In additional studies, the infiltration of macrophages and dendritic cells into CED-treated animals were increased compared with those in IV-treated animals, suggesting a highly active inflammatory response taking place in CED-treated mice.

CONCLUSIONS

The administration of bevacizumab via CED increases survival over that of treatment with IV bevacizumab. Thus, CED of bevacizumab alone or in combination with chemotherapy can be an effective protocol for treating gliomas.

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Encouse B. Golden, Hee-Yeon Cho, Florence M. Hofman, Stan G. Louie, Axel H. Schönthal and Thomas C. Chen

OBJECT

Chloroquine (CQ) is a quinoline-based drug widely used for the prevention and treatment of malaria. More recent studies have provided evidence that this drug may also harbor antitumor properties, whereby CQ possesses the ability to accumulate in lysosomes and blocks the cellular process of autophagy. Therefore, the authors of this study set out to investigate whether CQ analogs, in particular clinically established antimalaria drugs, would also be able to exert antitumor properties, with a specific focus on glioma cells.

METHODS

Toward this goal, the authors treated different glioma cell lines with quinine (QN), quinacrine (QNX), mefloquine (MFQ), and hydroxychloroquine (HCQ) and investigated endoplasmic reticulum (ER) stress–induced cell death, autophagy, and cell death.

RESULTS

All agents blocked cellular autophagy and exerted cytotoxic effects on drug-sensitive and drug-resistant glioma cells with varying degrees of potency (QNX > MFQ > HCQ > CQ > QN). Furthermore, all quinoline-based drugs killed glioma cells that were highly resistant to temozolomide (TMZ), the current standard of care for patients with glioma. The cytotoxic mechanism involved the induction of apoptosis and ER stress, as indicated by poly(ADP-ribose) polymerase (PARP) cleavage and CHOP/GADD153. The induction of ER stress and resulting apoptosis could be confirmed in the in vivo setting, in which tumor tissues from animals treated with quinoline-based drugs showed increased expression of CHOP/GADD153, along with elevated TUNEL staining, a measure of apoptosis.

CONCLUSIONS

Thus, the antimalarial compounds investigated in this study hold promise as a novel class of autophagy inhibitors for the treatment of newly diagnosed TMZ-sensitive and recurrent TMZ-resistant gliomas.

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Encouse B. Golden, Hee-Yeon Cho, Ardeshir Jahanian, Florence M. Hofman, Stan G. Louie, Axel H. Schönthal and Thomas C. Chen

Object

In a recent clinical trial, patients with newly diagnosed glioblastoma multiforme benefited from chloroquine (CQ) in combination with conventional therapy (resection, temozolomide [TMZ], and radiation therapy). In the present study, the authors report the mechanism by which CQ enhances the therapeutic efficacy of TMZ to aid future studies aimed at improving this therapeutic regimen.

Methods

Using in vitro and in vivo experiments, the authors determined the mechanism by which CQ enhances TMZ cytotoxicity. They focused on the inhibition-of-autophagy mechanism of CQ by knockdown of the autophagy-associated proteins or treatment with autophagy inhibitors. This mechanism was tested using an in vivo model with subcutaneously implanted U87MG tumors from mice treated with CQ in combination with TMZ.

Results

Knockdown of the autophagy-associated proteins (GRP78 and Beclin) or treatment with the autophagy inhibitor, 3-methyl adenine (3-MA), blocked autophagosome formation and reduced CQ cytotoxicity, suggesting that autophagosome accumulation precedes CQ-induced cell death. In contrast, blocking autophagosome formation with knockdown of GRP78 or treatment with 3-MA enhanced TMZ cytotoxicity, suggesting that the autophagy pathway protects from TMZ-induced cytotoxicity. CQ in combination with TMZ significantly increased the amounts of LC3B-II (a marker for autophagosome levels), CHOP/GADD-153, and cleaved PARP (a marker for apoptosis) over those with untreated or individual drug-treated glioma cells. These molecular mechanisms seemed to take place in vivo as well. Subcutaneously implanted U87MG tumors from mice treated with CQ in combination with TMZ displayed higher levels of CHOP/GADD-153 than did untreated or individual drug-treated tumors.

Conclusions

Taken together, these results demonstrate that CQ blocks autophagy and triggers endoplasmic reticulum stress, thereby increasing the chemosensitivity of glioma cells to TMZ.

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Mitchel S. Berger, Jeffrey N. Bruce, Thomas C. Chen and Gelareh Zadeh

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Xiao Chang, Lingling Shi, Fan Gao, Jonathan Russin, Liyun Zeng, Shuhan He, Thomas C. Chen, Steven L. Giannotta, Daniel J. Weisenberger, Gabriel Zada, Kai Wang and William J. Mack

Object

Meningiomas are among the most common primary adult brain tumors. Although typically benign, roughly 2%–5% display malignant pathological features. The key molecular pathways involved in malignant transformation remain to be determined.

Methods

Illumina expression microarrays were used to assess gene expression levels, and Illumina single-nucleotide polymorphism arrays were used to identify copy number variants in benign, atypical, and malignant meningiomas (19 tumors, including 4 malignant ones). The authors also reanalyzed 2 expression data sets generated on Affymetrix microarrays (n = 68, including 6 malignant ones; n = 56, including 3 malignant ones). A weighted gene coexpression network approach was used to identify coexpression modules associated with malignancy.

Results

At the genomic level, malignant meningiomas had more chromosomal losses than atypical and benign meningiomas, with average length of 528, 203, and 34 megabases, respectively. Monosomic loss of chromosome 22 was confirmed to be one of the primary chromosomal level abnormalities in all subtypes of meningiomas. At the transcriptome level, the authors identified 23 coexpression modules from the weighted gene coexpression network. Gene functional enrichment analysis highlighted a module with 356 genes that was highly related to tumorigenesis. Four intramodular hubs within the module (GAB2, KLF2, ID1, and CTF1) were oncogenic in other cancers such as leukemia. A putative meningioma tumor suppressor MN1 was also identified in this module with differential expression between malignant and benign meningiomas.

Conclusions

The authors' genomic and transcriptome analysis of meningiomas provides novel insights into the molecular pathways involved in malignant transformation of meningiomas, with implications for molecular heterogeneity of the disease.

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Martin H. Pham, Gabriel Zada, Gina M. Mosich, Thomas C. Chen, Steven L. Giannotta, Kai Wang and William J. Mack

Although a majority of meningiomas are benign neoplasms, those occurring at the cranial base may be challenging tumors to treat because of extensive tissue invasion, an inability to achieve gross-total microscopic resection, and local tumor recurrence and/or progression. A more comprehensive understanding of the genetic abnormalities associated with meningioma tumorigenesis, growth, and invasion may provide novel targets for grading assessments and individualizing molecular therapies for skull base meningiomas. The authors performed a review of the current literature to identify genes that have been associated with the formation and/or progression of meningiomas. Mutations in the NF2 gene have been most commonly implicated in the formation of the majority of meningiomas. Inactivation of other tumor suppressor genes, including DAL-1 and various tissue inhibitors of matrix metalloproteinases, upregulation of several oncogenes including c-sis and STAT3, and signaling dysregulation of pathways such as the Wnt pathway, have each been found to play important, and perhaps, complementary roles in meningioma development, progression, and recurrence. Identification of these genetic factors using genome-wide association studies and high-throughput genomics may provide data for future individualized treatment strategies.