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1.  Convection-Enhanced Delivery for Targeted Delivery of Antiglioma Agents: The Translational Experience 
Journal of Drug Delivery  2013;2013:107573.
Recent improvements in the understanding of glioblastoma (GBM) have allowed for increased ability to develop specific, targeted therapies. In parallel, however, there is a need for effective methods of delivery to circumvent the therapeutic obstacles presented by the blood-brain barrier and systemic side effects. The ideal delivery system should allow for adequate targeting of the tumor while minimizing systemic exposure, applicability across a wide range of potential therapies, and have existing safe and efficacious systems that allow for widespread application. Though many alternatives to systemic delivery have been developed, this paper will focus on our experience with convection-enhanced delivery (CED) and our focus on translating this technology from pre-clinical studies to the treatment of human GBM.
PMCID: PMC3586495  PMID: 23476784
2.  Prolonged intracerebral convection-enhanced delivery of topotecan with a subcutaneously implantable infusion pump 
Neuro-Oncology  2011;13(8):886-893.
Intracerebral convection-enhanced delivery (CED) of chemotherapeutic agents currently requires an externalized catheter and infusion system, which limits its duration because of the need for hospitalization and the risk of infection. To evaluate the feasibility of prolonged topotecan administration by CED in a large animal brain with the use of a subcutaneous implantable pump. Medtronic Synchromed-II pumps were implanted subcutaneously for intracerebral CED in pigs. Gadodiamide (28.7 mg/mL), with or without topotecan (136 μM), was infused at 0.7 mL/24 h for 3 or 10 days. Pigs underwent magnetic resonance imaging before and at 6 times points after surgery. Enhancement and FLAIR+ volumes were calculated in a semi-automated fashion. Magnetic resonance spectroscopy-based topotecan signature was also investigated. Brain histology was analyzed by hematoxylin and eosin staining and with immunoperoxidase for a microglial antigen. CED of topotecan/gadolinium was well tolerated in all cases (n = 6). Maximum enhancement volume was reached at day 3 and remained stable if CED was continued for 10 days, but it decreased if CED was stopped at day 3. Magnetic resonance spectroscopy revealed a decrease in parenchymal metabolites in the presence of topotecan. Similarly, the combination of topotecan and gadolinium infusion led to a FLAIR+ volume that tended to be larger than that seen after the infusion of gadolinium alone. Histological analysis of the brains showed an area of macrophage infiltrate in the ipsilateral white matter upon infusion with topotecan/gadolinium. Intracerebral topotecan CED is well tolerated in a large animal brain for up to 10 days. Intracerebral long-term CED can be achieved with a subcutaneously implanted pump and provides a stable volume of distribution. This work constitutes a proof of principle for the safety and feasibility for prolonged CED, providing a means of continuous local drug delivery that is accessible to the practicing neuro-oncologist.
PMCID: PMC3145467  PMID: 21750007
brain tumor; convection-enhanced delivery; glioma; infusion; local delivery; topotecan
3.  Convection-enhanced delivery of topotecan into a PDGF-driven model of glioblastoma prolongs survival, ablates tumor initiating cells and recruited glial progenitors 
Cancer research  2011;71(11):3963-3971.
The contribution of microenvironment to tumor growth has important implications for optimizing chemotherapeutic response and understanding the biology of recurrent tumors. In this study, we tested the effects of locally administered topotecan on a rat model of glioblastoma that is induced by intracerebral injection of PDGF-IRES-GFP-expressing retrovirus, we treated the tumors by convection-enhanced delivery (CED) of topotecan (136 μM) for 1, 4, or 7 days and then characterized the effects on both the retrovirus-transformed tumor cells (GFP+ cells) as well as the uninfected glial progenitor cells (GFP- cells) that are recruited to the tumor. Topotecan treatment reduced GFP+ cells ~10-fold and recruited progenitors by ~80-fold while providing a significant survival advantage that improved with greater treatment duration. Regions of glial progenitor ablation occurred corresponding to the anatomical distribution of topotecan as predicted by MRI of a surrogate tracer. Histopathologic changes in recurrent tumors point to a decrease in recruitment, most likely due to the chemotherapeutic ablation of the recruitable progenitor pool.
PMCID: PMC3113406  PMID: 21464045
Glioma; Glioblastoma; Topotecan; Convection Enhanced Delivery; progenitor
4.  Ribosome Profiling Reveals a Cell-Type-Specific Translational Landscape in Brain Tumors 
The Journal of Neuroscience  2014;34(33):10924-10936.
Glioma growth is driven by signaling that ultimately regulates protein synthesis. Gliomas are also complex at the cellular level and involve multiple cell types, including transformed and reactive cells in the brain tumor microenvironment. The distinct functions of the various cell types likely lead to different requirements and regulatory paradigms for protein synthesis. Proneural gliomas can arise from transformation of glial progenitors that are driven to proliferate via mitogenic signaling that affects translation. To investigate translational regulation in this system, we developed a RiboTag glioma mouse model that enables cell-type-specific, genome-wide ribosome profiling of tumor tissue. Infecting glial progenitors with Cre-recombinant retrovirus simultaneously activates expression of tagged ribosomes and delivers a tumor-initiating mutation. Remarkably, we find that although genes specific to transformed cells are highly translated, their translation efficiencies are low compared with normal brain. Ribosome positioning reveals sequence-dependent regulation of ribosomal activity in 5′-leaders upstream of annotated start codons, leading to differential translation in glioma compared with normal brain. Additionally, although transformed cells express a proneural signature, untransformed tumor-associated cells, including reactive astrocytes and microglia, express a mesenchymal signature. Finally, we observe the same phenomena in human disease by combining ribosome profiling of human proneural tumor and non-neoplastic brain tissue with computational deconvolution to assess cell-type-specific translational regulation.
PMCID: PMC4131009  PMID: 25122893
cell-type-specific expression; glioblastoma; glioma; ribosome profiling; translational regulation
5.  MDA-9/syntenin is a key regulator of glioma pathogenesis 
Neuro-Oncology  2013;16(1):50-61.
The extraordinary invasiveness of human glioblastoma multiforme (GBM) contributes to treatment failure and the grim prognosis of patients diagnosed with this tumor. Consequently, it is imperative to define further the cellular mechanisms that control GBM invasion and identify promising novel therapeutic targets. Melanoma differentiation associated gene–9 (MDA-9/syntenin) is a highly conserved PDZ domain–containing scaffolding protein that promotes invasion and metastasis in vitro and in vivo in human melanoma models. To determine whether MDA-9/syntenin is a relevant target in GBM, we investigated its expression in tumor samples and involvement in GBM invasion and angiogenesis.
We assessed MDA-9/syntenin levels in available databases, patient tumor samples, and human-derived cell lines. Through gain-of-function and loss-of-function studies, we analyzed changes in invasion, angiogenesis, and signaling in vitro. We used orthotopic xenografts with GBM6 cells to demonstrate the role of MDA-9/syntenin in GBM pathogenesis in vivo.
MDA-9/syntenin expression in high-grade astrocytomas is significantly higher than normal tissue counterparts. Forced overexpression of MDA-9/syntenin enhanced Matrigel invasion, while knockdown inhibited invasion, migration, and anchorage-independent growth in soft agar. Moreover, overexpression of MDA-9/syntenin increased activation of c-Src, p38 mitogen-activated protein kinase, and nuclear factor kappa-B, leading to elevated expression of matrix metalloproteinase 2 and secretion of interleukin-8 with corresponding changes observed upon knockdown. GBM6 cells that stably express small hairpin RNA for MDA-9/syntenin formed smaller tumors and had a less invasive phenotype in vivo.
Our findings indicate that MDA-9/syntenin is a novel and important mediator of invasion in GBM and a key regulator of pathogenesis, and we identify it as a potential target for anti-invasive treatment in human astrocytoma.
PMCID: PMC3870820  PMID: 24305713
MDA-9/syntenin; GBM; glioma; invasion; intracranial injection
6.  Heat-shock protein peptide complex–96 vaccination for recurrent glioblastoma: a phase II, single-arm trial 
Neuro-Oncology  2013;16(2):274-279.
Outcomes for patients with recurrent glioblastoma multiforme (GBM) are poor and may be improved by immunotherapy. We investigated the safety and efficacy of an autologous heat-shock protein peptide complex–96 (HSPPC-96) vaccine for patients with recurrent GBM.
In this open-label, single-arm, phase II study, adult patients with surgically resectable recurrent GBM were given vaccine after gross total resection. The primary endpoint was overall survival at 6 months. Secondary endpoints included overall survival, progression-free survival, safety, and immune profiling. Outcome analyses were performed in the intention-to-treat and efficacy populations.
Between October 3, 2007 and October 24, 2011, 41 patients underwent gross total resection of recurrent GBM and received a median of 6 doses of HSPPC-96 vaccine. Following treatment, 90.2% of patients were alive at 6 months (95% confidence interval [CI]: 75.9–96.8) and 29.3% were alive at 12 months (95% CI: 16.6–45.7). Median overall survival was 42.6 weeks (95% CI: 34.7–50.5). Twenty-seven (66%) patients were lymphopenic prior to therapy, and patients with lymphocyte counts below the cohort median demonstrated decreased overall survival (hazard ratio: 4.0; 95% CI: 1.4–11.8; P = .012). There were no treatment-related deaths. There were 37 serious (grades 3–5) adverse events reported, with 17 attributable to surgical resection and a single grade 3 constitutional event related to the vaccine.
The HSPPC-96 vaccine is safe and warrants further study of efficacy for the treatment of recurrent GBM. Significant pretreatment lymphopenia may impact the outcomes of immunotherapy and deserves additional investigation.
PMCID: PMC3895386  PMID: 24335700
glioblastoma; heat-shock proteins; immunotherapy
7.  The immune cell infiltrate populating meningiomas is composed of mature, antigen-experienced T and B cells 
Neuro-Oncology  2013;15(11):1479-1490.
Meningiomas often harbor an immune cell infiltrate that can include substantial numbers of T and B cells. However, their phenotype and characteristics remain undefined. To gain a deeper understanding of the T and B cell repertoire in this tumor, we characterized the immune infiltrate of 28 resected meningiomas representing all grades.
Immunohistochemistry was used to grossly characterize and enumerate infiltrating lymphocytes. A molecular analysis of the immunoglobulin variable region of tumor-infiltrating B cells was used to characterize their antigen experience. Flow cytometry of fresh tissue homogenate and paired peripheral blood lymphocytes was used to identify T cell phenotypes and characterize the T cell repertoire.
A conspicuous B and T cell infiltrate, primarily clustered in perivascular spaces, was present in the microenvironment of most tumors examined. Characterization of 294 tumor-infiltrating B cells revealed clear evidence of antigen experience, in that the cardinal features of an antigen-driven B cell response were present. Meningiomas harbored populations of antigen-experienced CD4+ and CD8+ memory/effector T cells, regulatory T cells, and T cells expressing the immune checkpoint molecules PD-1 and Tim-3, indicative of exhaustion. All of these phenotypes were considerably enriched relative to their frequency in the circulation. The T cell repertoire in the tumor microenvironment included populations that were not reflected in paired peripheral blood.
The tumor microenvironment of meningiomas often includes postgerminal center B cell populations. These tumors invariably include a selected, antigen-experienced, effector T cell population enriched by those that express markers of an exhausted phenotype.
PMCID: PMC3813416  PMID: 23978377
B cell; meningioma; T cell; tumor-infiltrating lymphocytes
8.  Patient-Specific Metrics of Invasiveness Reveal Significant Prognostic Benefit of Resection in a Predictable Subset of Gliomas 
PLoS ONE  2014;9(10):e99057.
Malignant gliomas are incurable, primary brain neoplasms noted for their potential to extensively invade brain parenchyma. Current methods of clinical imaging do not elucidate the full extent of brain invasion, making it difficult to predict which, if any, patients are likely to benefit from gross total resection. Our goal was to apply a mathematical modeling approach to estimate the overall tumor invasiveness on a patient-by-patient basis and determine whether gross total resection would improve survival in patients with relatively less invasive gliomas.
In 243 patients presenting with contrast-enhancing gliomas, estimates of the relative invasiveness of each patient's tumor, in terms of the ratio of net proliferation rate of the glioma cells to their net dispersal rate, were derived by applying a patient-specific mathematical model to routine pretreatment MR imaging. The effect of varying degrees of extent of resection on overall survival was assessed for cohorts of patients grouped by tumor invasiveness.
We demonstrate that patients with more diffuse tumors showed no survival benefit (P = 0.532) from gross total resection over subtotal/biopsy, while those with nodular (less diffuse) tumors showed a significant benefit (P = 0.00142) with a striking median survival benefit of over eight months compared to sub-totally resected tumors in the same cohort (an 80% improvement in survival time for GTR only seen for nodular tumors).
These results suggest that our patient-specific, model-based estimates of tumor invasiveness have clinical utility in surgical decision making. Quantification of relative invasiveness assessed from routinely obtained pre-operative imaging provides a practical predictor of the benefit of gross total resection.
PMCID: PMC4211670  PMID: 25350742
9.  Inconsistent blood brain barrier disruption by intraarterial mannitol in rabbits: implications for chemotherapy 
Journal of neuro-oncology  2010;104(1):11-19.
The novel ability to quantify drug and tracer concentrations in vivo by optical means leads to the possibility of detecting and quantifying blood brain barrier (BBB) disruption in real-time by monitoring concentrations of chromophores such as Evan's Blue. In this study, experiments were conducted to assess the disruption of the BBB, by intraarterial injection of mannitol, in New Zealand white rabbits. Surgical preparation included: tracheotomy for mechanical ventilation, femoral and selective internal carotid artery (ICA) catheterizations, skull screws for monitoring electrocerebral activity, bilateral placement of laser Doppler probes and a small craniotomy for the placement of a fiber optic probe to determine tissue Evan's Blue dye concentrations. Evan's Blue (6.5 mg/kg) was injected intravenously (IV) just before BBB disruption with intracarotid mannitol (25%, 8 ml/40 s). Brain tissue concentrations of the dye in mannitol-treated and control animals were monitored using the method of optical pharmacokinetics (OP) during the subsequent 60 min. Hemo-dynamic parameters, heart rate, blood pressure, and EKG remained stable throughout the experiments in both the control and the mannitol-treated group. Brain tissue concentrations of Evan's Blue and the brain:plasma Evan's Blue partition coefficient progressively increased during the period of observation. A wide variation in brain tissue Evan's Blue concentrations was observed in the mannitol group. The experiments demonstrate the feasibility of measuring tissue concentrations of Evan's Blue without invading the brain parenchyma, and in real-time. The data suggest that there are significant variations in the degree and duration of BBB disruption induced with intraarterial mannitol. The ability to optically monitor the BBB disruption in real-time could provide a feedback control for hypertonic disruption and/or facilitate dosage control for chemotherapeutic drugs that require such disruption.
PMCID: PMC4013427  PMID: 21153681
Blood brain barrier disruption; Intraarterial; Mannitol
10.  Murine Cell Line Model of Proneural Glioma for Evaluation of Anti-Tumor Therapies 
Journal of neuro-oncology  2013;112(3):375-382.
Molecular subtypes of glioblastoma (GBM) with distinct alterations have been identified. There is need for reproducible, versatile preclinical models that resemble specific GBM phenotypes to facilitate preclinical testing of novel therapies. We present a cell line-based murine Proneural GBM model and characterize its response to radiation therapy.
Proneural gliomas were generated by injecting PDGF-IRES-Cre retrovirus into the subcortical white matter of adult mice that harbor floxed tumor suppressors (Pten and p53) and stop-floxed reporters. Primary cell cultures were generated from the retrovirus induced tumors and maintained in vitro for multiple passages. RNA sequencing-based expression profiling of the resulting cell lines was performed. The tumorigenic potential of the cells was assessed by intracranial injection into adult naïve mice from different strains. Tumor growth was assessed by bioluminescence imaging (BLI). BLI for tumor cells and brain slices were obtained and compared to in vivo BLI. Response to whole-brain radiation was assessed in glioma-bearing animals.
Intracranial injection of Pdgf+Pten−/−p53−/−luciferase+ glioma cells led to formation of GBM-like tumors with 100% efficiency (n=48) and tumorigenesis was retained for more than 3 generations. The cell lines specifically resembled Proneural GBM based on expression profiling by RNA-Seq. Pdgf+Pten−/−p53−/−luciferase+ cell number correlated with BLI signal. Serial BLI measured tumor growth and correlated with size and location by ex-vivo imaging. Moreover, BLI predicted tumor-related mortality with a 93% risk of death within 5 days following a BLI signal between 1×108−5×108 photons/sec/cm2. BLI signal had transient but significant response following radiotherapy, which corresponded to a modest survival benefit for radiated mice (p<0.05).
Intracranial injection of Pdgf+Pten−/−p53−/−luciferase+ cells constitutes a novel and highly reproducible model, recapitulating key features of human Proneural GBM, and can be used to evaluate tumor-growth and response to therapy.
PMCID: PMC3694577  PMID: 23504257
glioma; proneural; murine; radiotherapy; cell line
11.  The integrated landscape of driver genomic alterations in glioblastoma 
Nature genetics  2013;45(10):1141-1149.
Glioblastoma remains one of the most challenging forms of cancer to treat. Here, we develop a computational platform that integrates the analysis of copy number variations and somatic mutations and unravels the landscape of in-frame gene fusions in glioblastoma. We find mutations with loss of heterozygosity of LZTR-1, an adaptor of Cul3-containing E3 ligase complexes. Mutations and deletions disrupt LZTR-1 function, which restrains self-renewal and growth of glioma spheres retaining stem cell features. Loss-of-function mutations of CTNND2 target a neural-specific gene and are associated with transformation of glioma cells along the very aggressive mesenchymal phenotype. We also report recurrent translocations that fuse the coding sequence of EGFR to several partners, with EGFR-SEPT14 as the most frequent functional gene fusion in human glioblastoma. EGFR-SEPT14 fusions activate Stat3 signaling and confer mitogen independency and sensitivity to EGFR inhibition. These results provide important insights into the pathogenesis of glioblastoma and highlight new targets for therapeutic intervention.
PMCID: PMC3799953  PMID: 23917401
12.  MicroRNA-21 silencing enhances the cytotoxic effect of the antiangiogenic drug sunitinib in glioblastoma 
Human Molecular Genetics  2012;22(5):904-918.
Highly malignant glioblastoma (GBM) is characterized by high genetic heterogeneity and infiltrative brain invasion patterns, and aberrant miRNA expression has been associated with hallmark malignant properties of GBM. The lack of effective GBM treatment options prompted us to investigate whether miRNAs would constitute promising therapeutic targets toward the generation of a gene therapy approach with clinical significance for this disease. Here, we show that microRNA-21 (miR-21) is upregulated and microRNA-128 (miR-128) is downregulated in mouse and human GBM samples, a finding that is corroborated by analysis of a large set of human GBM data from The Cancer Genome Atlas. Moreover, we demonstrate that oligonucleotide-mediated miR-21 silencing in U87 human GBM cells resulted in increased levels of the tumor suppressors PTEN and PDCD4, caspase 3/7 activation and decreased tumor cell proliferation. Cell exposure to pifithrin, an inhibitor of p53 transcriptional activity, reduced the caspase activity associated with decreased miR-21 expression. Finally, we demonstrate for the first time that miR-21 silencing enhances the antitumoral effect of the tyrosine kinase inhibitor sunitinib, whereas no therapeutic benefit is observed when coupling miR-21 silencing with the first-line drug temozolomide. Overall, our results provide evidence that miR-21 is uniformly overexpressed in GBM and constitutes a highly promising target for multimodal therapeutic approaches toward GBM.
PMCID: PMC3561912  PMID: 23201752
13.  Epithelioid Pituicytoma 
World neurosurgery  2011;78(0):191.E1-191.E7.
Pituicytomas are rare tumors of the sellar region that are derived from specialized glial cells called pituicytes. They characteristically exhibit spindle cell features and fascicular or storiform patterns of growth. No other histological variants of this tumor have been described.
Case Description
Here we report a diagnostically challenging case of pituicytoma in a 42 year-old man with a sellar mass arising from the pituitary stalk. On histological examination, the tumor displayed an epithelioid histoarchitecture with no characteristic spindle cell or fascicular growth features. Strong immunopositivity for the pituicyte marker thyroid transcription factor-1 (TTF-1) within tumor cells proved essential for diagnosing this unusual pituicytoma variant.
Pituicytomas may display epithelioid rather than fascicular or storiform histoarchitecture. Epithelioid pituicytoma variants may be diagnosed in cases such as ours where both the clinical findings and immunohistochemical analysis suggest a tumor derived from pituicytes.
PMCID: PMC3926508  PMID: 22120271
brain tumor; low grade glioma; neurohypophysis; pituicytoma; thyroid transcription factor-1 (TTF-1)
14.  Platelet-derived growth factor receptor (PDGFR) expression in primary spinal cord gliomas 
Journal of neuro-oncology  2011;106(2):10.1007/s11060-011-0666-6.
Abnormal signaling through the platelet-derived growth factor receptor (PDGFR) has been proposed as a possible mechanism of spinal cord glioma initiation and progression. However, the extent of PDGFR expression in human spinal cord gliomas remains unknown. In this study we perform immunohistochemical analysis of PDGFRα expression in a series of 33 primary intramedullary spinal cord gliomas of different types and grades. PDGFRα was seen to be expressed in a significant subset of these tumors across all major glioma types including ependymoma, oligodendroglioma, pilocytic astrocytoma, astrocytoma, and glioblastoma. These results support the hypothesis that growth factor signaling through the PDGFR may be important for the development of at least a subset of human spinal cord gliomas. Further studies investigating the prognostic significance of PDGFR expression as well as the role of PDGF signaling on the development of intramedullary spinal cord gliomas are warranted.
PMCID: PMC3869991  PMID: 21789698
Astrocytoma; Ependymoma; Glioblastoma multiforme; Glioma; Intramedullary; Oligodendroglioma; Pilocytic; Spinal cord; Tumor
15.  Retroviral Delivery of Platelet-Derived Growth Factor to Spinal Cord Progenitor Cells Drives the Formation of Intramedullary Gliomas 
Neurosurgery  2012;70(1):10.1227/NEU.0b013e31822ce963.
High-grade gliomas of the spinal cord are poorly understood tumors that are very commonly associated with bad outcomes. The transforming effects of platelet-derived growth factor (PDGF) on spinal cord glial progenitor cells may play an important role in the development of these tumors.
To investigate the possible tumor-initiating effects of PDGF overexpression in the spinal cord, we delivered a PDGF retrovirus directly into the substance of the spinal cord.
The spinal cords of wild-type adult rats were surgically exposed and injected with 106 colony-forming units of a green fluorescent protein-tagged, PDGF-expressing retrovirus. A control virus was injected to assess the cell types that become infected during retroviral delivery to the spinal cord.
It was observed that PDGF overexpression in the spinal cord causes morbidity from high-grade intramedullary glioma formation between 27 and 49 days after PDGF retrovirus injection. Retroviral transduction was highly efficient with 100% of injected animals displaying the tumor phenotype. The tumors produced were highly proliferative, were locally invasive, and displayed the immunophenotype of virus-targeted glial progenitor cells (Olig2+PDGFR+NG2+GFAP−).
PDGF is capable of driving glial progenitor cells within the adult spinal cord to form high-grade gliomas. Further investigation of PDGF signaling in the spinal cord is needed to better understand and treat these devastating tumors.
PMCID: PMC3869993  PMID: 21760556
Astrocytoma; Ependymoma; Glioma; NG2; Platelet-derived growth factor; Spinal cord tumor; Stem cell
16.  PDGF-B-mediated downregulation of miR-21: new insights into PDGF signaling in glioblastoma 
Human Molecular Genetics  2012;21(23):5118-5130.
Glioblastoma (GBM) is a highly heterogeneous type of tumor characterized by genomic and signaling abnormalities affecting pathways involved in control of cell fate, including tumor-suppressor- and growth factor-regulated pathways. An aberrant miRNA expression has been observed in GBM, being associated with impaired cellular functions resulting in malignant transformation, proliferation and invasion. Here, we demonstrate for the first time that platelet-derived growth factor-B (PDGF-B), a potent angiogenic growth factor involved in GBM development and progression, promotes downregulation of pro-oncogenic (miR-21) and anti-oncogenic (miR-128) miRNAs, as well as upregulation/downregulation of several miRNAs involved in GBM pathology. Retrovirally mediated overexpression of PDGF-B in U87 human GBM cells or their prolonged exposure, as well as that of F98 rat glioma cells to this ligand, resulted in decreased miR-21 and miR-128 levels, which was associated with increased cell proliferation. Furthermore, siRNA-mediated PDGF-B silencing led to increased levels of miR-21 and miR-128, while miRNA modulation through overexpression of miR-21 did not alter the levels of PDGF-B. Finally, we demonstrate that modulation of tumor suppressors PTEN and p53 in U87 cells does not affect the decrease in miR-21 levels associated with PDGF-B overexpression. Overall, our findings suggest that, besides its role in inducing GBM tumorigenesis, PDGF-B may enhance tumor proliferation by modulating the expression of oncomiRs and tumor suppressor miRNAs in U87 human GBM cells.
PMCID: PMC3490519  PMID: 22922228
18.  The Addition of Sunitinib to Radiation Delays Tumor Growth in a Murine Model of Glioblastoma 
Neurological research  2012;34(3):10.1179/1743132812Y.0000000005.
Recent preclinical studies suggest that treating glioblastoma (GBM) with a combination of targeted chemotherapy and radiotherapy may enhance the anti-tumor effects of both therapies. However, the effects of these treatments on glioma growth and progression are poorly understood.
In this study we have tested the effects of combination therapy in a mouse glioma model that utilizes a PDGF-IRES-Cre-expressing retrovirus to infect adult glial progenitors in mice carrying conditional deletions of Pten and p53. This model produces tumors with the histological features of GBM with 100% penetrance, making it a powerful system to test novel treatments. Sunitinib is an orally active, small molecule inhibitor of multiple receptor tyrosine kinases (RTKs) critical for tumor growth and angiogenesis, including PDGF receptors. We investigate the addition of Sunitinib to radiotherapy, and use bioluminescence imaging to characterize the effects of treatment on glioma growth and progression.
Treating our PDGF-driven mouse model with either Sunitinib or high-dose radiation alone delayed tumor growth and had a modest but significant effect on survival, while treating with low-dose radiation alone failed to control glioma growth and progression. The addition of Sunitinib to low-dose radiation caused a modest, but significant delay in tumor growth. However, no significant survival benefit was seen as tumors progressed in 100% of animals. Histological analysis revealed a reduction in vascular proliferation and a marked increase in brain invasion. An additional study combining Sunitinib with high-dose radiation revealed a fatal toxicity despite individual monotherapies being well tolerated.
These results show that the addition of Sunitinib to radiotherapy fails to significantly alter survival in GBM despite enhancement of the effects of radiation. Furthermore, an enhanced risk of toxicity associated with combined therapy must be considered in the design of future clinical studies.
PMCID: PMC3812673  PMID: 22449730
glioblastoma; PDGF; radiation; radiotherapy; sunitinib; sutent; SU1128; VEGF
19.  Inhibition of Caveolin-1 Restores Myeloid Cell Function in Human Glioblastoma 
PLoS ONE  2013;8(10):e77397.
Gliomas are the most common primary brain tumor in both children and adults. The prognosis for glioblastoma (GBM), the most common type of malignant glioma, has remained dismal, with median survival a little over one year despite maximal therapy with surgery, chemotherapy, and radiation. Although immunotherapy has become increasingly successful against many systemic tumors, clinical efficacy against brain tumors has been limited. One reason for this is an incomplete understanding of the local immunologic tumor microenvironment, particularly the function of large numbers of infiltrating myeloid derived cells. Monocytes/microglia are myeloid derived immunomodulatory cells, and they represent the predominant infiltrating immune cell population in gliomas. Our group has previously demonstrated using complementary in vitro and in vivo approaches that GBM tumor cells polarize tumor-associated myeloid cells (TAMs) and suppress their immunostimulatory function.
Methods and Results
To better understand the mechanisms responsible for this immunosuppression, we used gene expression profiling of stimulated monocytes in the presence or absence of GBM tumor cells. Our analysis identified caveolin-1 (CAV1), a plasma membrane molecule with pleiotropic functions, as significantly up-regulated in monocytes in the presence of GBMs. We validated these findings ex vivo by confirming up-regulation of CAV1 in TAMs isolated from GBMs immediately after surgical resection. Finally, we demonstrate that siRNA inhibition of CAV1 restores myeloid cell function, as measured by TNF-alpha secretion, in the presence of GBMs.
Restoration of TAM function through pharmacologic blockage of CAV1 may facilitate more successful immunotherapeutic strategies directed against a variety of solid human tumors infiltrated by TAMs.
PMCID: PMC3793958  PMID: 24130882
20.  Magnetic Resonance Imaging Characteristics of Glioblastoma Multiforme: Implications for Understanding Glioma Ontogeny 
Neurosurgery  2010;67(5):1319-1328.
Identifying the origin of gliomas carries important implications for advancing the treatment of these recalcitrant tumors. Recent research promotes the hypothesis of a subventricular zone (SVZ) origin for the stemlike gliomagenic cells identified within human glioma specimens. However, conflicting evidence suggests that SVZ-like cells are not uniquely gliomagenic but this capacity may be shared by cycling progenitors distributed throughout the subcortical white matter (SCWM).
To review radiological evidence in glioblastoma multiforme (GBM) patients to provide insight into the question of glioma ontogeny.
We explored whether GBMs at first diagnosis demonstrated a pattern of anatomic distribution consistent with origin at the SVZ through retrospective analysis of preoperative contrast-enhanced T1-weighted magnetic resonance images in 63 patients. We then examined the relationship of tumor volume, point of origin, and proximity to the ventricles using a computer model of glioma growth.
Fewer than half of the GBMs analyzed had contrast-enhancing portions that contacted the ventricle on preoperative imaging. A strong correlation was found between tumor volume and the distance between the contrast-enhancing edge of the tumor and the ventricle, demonstrating that tumors abutting the ventricle are significantly larger than those that do not. The lesions simulated by the computer model validated our assumption that tumors that are radiographically distant from the ventricles are unlikely to have originated in the SVZ and supported our hypothesis that as they grow, the edges of all tumors will near the ventricles, regardless of their point of origin.
This work offers further support for the hypothesis that the origins of GBMs are at sites distributed throughout the white matter and are not limited to the region of the SVZ.
PMCID: PMC3774031  PMID: 20871424
Cancer stem cell; Glioblastoma; Glioma; Glioma ontogeny
21.  Incidence, treatment and survival of patients with craniopharyngioma in the surveillance, epidemiology and end results program 
Neuro-Oncology  2012;14(8):1070-1078.
Craniopharyngioma is a rare primary central nervous system neoplasm. Our objective was to determine factors associated with incidence, treatment, and survival of craniopharyngiomas in the United States. We used the surveillance, epidemiology and end results program (SEER) database to identify patients who received a diagnosis of craniopharyngioma during 2004–2008. We analyzed clinical and demographic information, including age, race, sex, tumor histology, and treatment. Age-adjusted incidence rates and age, sex, and race-adjusted expected survival rates were calculated. We used Cox proportional hazards models to determine the association between covariates and overall survival. We identified 644 patients with a diagnosis of craniopharyngioma. Black race was associated with an age-adjusted relative risk for craniopharyngioma of 1.26 (95% confidence interval [CI], 0.98–1.59), compared with white race. One- and 3-year survival rates of 91.5% (95% CI, 88.9%–93.5%), and 86.2% (95% CI, 82.7%–89.0%) were observed for the cohort; relative survival rates were 92.1% (95% CI, 89.5%–94.0%) and 87.6% (95% CI, 84.1%–90.4%) for 1- and 3-years, respectively. In the multivariable model, factors associated with prolonged survival included younger age, smaller tumor size, subtotal resection, and radiation therapy. Black race, on the other hand, was associated with worse overall survival in the final model. We demonstrated that >85% of patients survived 3 years after diagnosis and that subtotal resection and radiation therapy were associated with prolonged survival. We also noted a higher incidence rate and worse 1- and 3-year survival rates in the black population. Future investigations should examine these racial disparities and focus on evaluating the efficacy of emerging treatment paradigms.
PMCID: PMC3408265  PMID: 22735773
benign tumor; craniopharyngioma; epidemiology; racial disparity; SEER
22.  Risks of pituitary surgery in the elderly 
Nature reviews. Endocrinology  2010;6(11):606-608.
Surgical resection of pituitary tumors is the treatment of choice for patients with hormone-secreting tumors or those that impair vision and other neurological functions. A recent study by Grossman et al., however, found transsphenoidal surgery to be associated with increased mortality and morbidities in elderly patients, which suggests the need for careful individualized decision-making in this vulnerable population.
PMCID: PMC3677229  PMID: 20962868
23.  A novel adenoviral vector labeled with superparamagnetic iron oxide nanoparticles for real-time tracking of viral delivery 
In vivo tracking of gene therapy vectors challenges the investigation and improvement of biodistribution of these agents in the brain, a key feature for their targeting of infiltrative malignant gliomas. The glioma-targeting Ad5/3-cRGD gene therapy vector was covalently bound to super-paramagnetic iron oxide (Fe3O4) nanoparticles (SPION) to monitor its distribution by MRI. Transduction of labeled and unlabeled vectors was assessed on the U87 glioma cell line and normal human astrocytes (NHA), and was higher in U87 compared to NHA, but was similar between labeled and unlabeled virus. An in vivo study was performed by intracranial subcortical injection of labeled-Ad5/3-cRGD particles into a pig brain. The labeled vector appeared in vivo as a T2-weighted hyperintensity and a T2-gradient echo signal at the injection site, persisting up to 72 hours post-injection. We describe a glioma-targeting vector that is labeled with SPION, thereby allowing for MRI detection with no change in transduction capability.
PMCID: PMC3572211  PMID: 22516547
Adenovirus; Gene therapy; Nanoparticle
24.  Tumor-Associated Macrophages in Glioma: Friend or Foe? 
Journal of Oncology  2013;2013:486912.
Tumor-associated macrophages (TAMs) contribute substantially to the tumor mass of gliomas and have been shown to play a major role in the creation of a tumor microenvironment that promotes tumor progression. Shortcomings of attempts at antiglioma immunotherapy may result from a failure to adequately address these effects. Emerging evidence supports an independent categorization of glioma TAMs as alternatively activated M2-type macrophages, in contrast to classically activated proinflammatory M1-type macrophages. These M2-type macrophages exert glioma-supportive effects through reduced anti-tumor functions, increased expression of immunosuppressive mediators, and nonimmune tumor promotion through expression of trophic and invasion-facilitating substances. Much of our work has demonstrated these features of glioma TAMs, and together with the supporting literature will be reviewed here. Additionally, the dynamics of glioma cell-TAM interaction over the course of tumor development remain poorly understood; our efforts to elucidate glioma cell-TAM dynamics are summarized. Finally, the molecular pathways which underlie M2-type TAM polarization and gene expression similarly require further investigation, and may present the most potent targets for immunotherapeutic intervention. Highlighting recent evidence implicating the transcription factor STAT3 in immunosuppressive tumorigenic glioma TAMs, we advocate for gene array-based approaches to identify yet unappreciated expression regulators and effector molecules important to M2-type glioma TAMs polarization and function within the glioma tumor microenvironment.
PMCID: PMC3664503  PMID: 23737783
25.  Temozolomide (Temodar®) and capecitabine (Xeloda®) treatment of an aggressive corticotroph pituitary tumor 
Pituitary  2011;14(4):418-424.
Only rarely do corticotroph pituitary tumors become invasive leading to symptoms caused by compression of cranial nerves and other local structures. When aggressive pituitary neuroendocrine tumors do develop, conventional treatment options are of limited success. A 50-year-old man developed a giant invasive corticotroph pituitary tumor 2 years after initial presentation. His tumor and symptoms failed to respond to maximal surgical, radio-surgical, radiation and medical therapy and a bilateral adrenalectomy was done. He subsequently developed rapid growth of his tumor leading to multiple cranial nerve deficits. He was administered salvage chemotherapy with capecitabine and temozolomide (CAPTEM), a novel oral chemotherapy regimen developed at our institution for treatment of neuroendocrine tumors. After two cycles of CAPTEM, his tumor markedly decreased in size and ACTH levels fell by almost 90%. Despite further decreases in ACTH levels, his tumor recurred after 5 months with increased avidity on PET scan suggesting a transformation to a more aggressive phenotype. Temozolomide had been reported to be effective against other pituitary tumors and this case adds to this literature demonstrating its use along with capecitabine (CAPTEM) against a corticotroph tumor. Further evaluation of the CAPTEM regimen in patients with pituitary neuroendocrine tumors which fail to respond to classic treatments is warranted.
PMCID: PMC2891584  PMID: 19960369

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