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1.  Tumor antigen precursor protein profiles of adult and pediatric brain tumors identify potential targets for immunotherapy 
Journal of neuro-oncology  2008;88(1):65-76.
Objectives
We evaluated and compared tumor antigen precursor protein (TAPP) profiles in adult and pediatric brain tumors of 31 genes related to tumor associated antigens (TAA) for possible use in immunotherapy. Antigens were selected based on their potential to stimulate T cell responses against tumors of neuroectodermal origin.
Methods
Thirty-seven brain tumor specimens from 11 adult and 26 pediatric patients were analyzed by quantitative real-time PCR for the relative expression of 31 TAPP mRNAs. The age range of adults (4F:7M) was 27–77 years (median 51.5 ± 14.5 years) and for pediatrics (12F:14M) was 0.9–19 years (median 8.3 ± 5.5 years). Histological diagnoses consisted of 16 glioblastomas, 4 low grade astrocytomas, 10 juvenile pilocytic astrocytomas, and 7 ependymomas.
Results
The adult gliomas expressed 94% (29 of 31) of the TAPP mRNAs evaluated compared with pediatric brain tumors that expressed 55–74% of the TAPP mRNAs, dependent on tumor histological subtype. Four types of TAPP expression patterns were observed: (1) equal expression among adult and pediatric cases, (2) greater expression in adult than pediatric cases, (3) expression restricted to adult GBM and (4) a random distribution. The pediatric brain tumors lacked expression of some genes associated with engendering tumor survival, such as hTert and Survivin.
Conclusions
The potential TAA targets identified from the TAPP profiles of 31 genes associated with adult and pediatric brain tumors may help investigators select specific target antigens for developing dendritic cell- or peptide-based vaccines or T cell-based immunotherapeutic approaches against brain tumors.
doi:10.1007/s11060-008-9534-4
PMCID: PMC4005736  PMID: 18259692
Glioma; Pediatric brain tumors; Tumor associated antigens; Immunotherapy
2.  Treatment of Pediatric Brain Tumors 
Journal of cellular physiology  2008;217(3):584-589.
Over the past decades considerable advances have been made in neurosurgery, radiotherapy and chemotherapy resulting in improved survival and cure rates for children with brain tumors. Here we review four of the most common subtypes of pediatric brain tumors, low-grade and high-grade astrocytomas, medulloblastomas and ependymomas, highlighting their molecular features regarding their tumor biology and promising potential therapeutic targets that may hold promise for finding new “molecularly targeted” drugs. Importantly, appropriate clinical trial design will play a critical role in the evaluation of new and novel treatment approaches for pediatric brain tumors.
doi:10.1002/jcp.21544
PMCID: PMC2574972  PMID: 18651562
3.  Antiangiogenic Effects of Noscapine Enhance Radioresponse for GL261 Tumors 
Purpose
To determine whether the tubulin-binding drug noscapine could enhance radiosensitivity of GL261 glioma tumors by inhibiting tumor angiogenesis.
Methods and Materials
The human T98G and murine GL261 glioma cell lines treated with noscapine, radiation, or both were assayed for clonogenic survival. Mice with established GL261 hind limb tumors were treated with noscapine, radiation or both to evaluate the effect of noscapine on radioresponse. In a separate experiment with the same treatment groups, 7 days after radiation tumors were resected and immunostained to measure proliferation rate, apoptosis and angiogenic activity.
Results
Noscapine reduced clonogenic survival without enhancement of radiosensitivity in vitro. Noscapine combined with radiation significantly increased tumor growth delay: 5, 8, 13, 18 days for control, noscapine alone, radiation alone, and the combination treatment, respectively (p < 0.001). To assess the effect of the combination of noscapine plus radiation on the tumor vasculature, tubule formation by the murine endothelial 2H11 cells was tested. Noscapine with radiation significantly inhibited tubule formation compared with radiation alone. By immunohistochemistry, tumors treated with the combination of noscapine plus radiation showed a decrease in BrdU incorporation, an increase in apoptosis by TUNEL and a decrease in tumor vessel density compared with tumors treated with radiation alone.
Conclusion
Noscapine enhanced the sensitivity of GL261 glioma tumors to radiation resulting in a significant tumor growth delay. These findings are clinically relevant, particularly in view of the mild toxicity profile of this drug.
doi:10.1016/j.ijrobp.2008.04.020
PMCID: PMC2572218  PMID: 18640497
Noscapine; glioma; GL261 mouse model; angiogenesis; radioresponse
4.  HGF upregulates CXCR4 expression in gliomas via NF-κB: Implications for glioma cell migration 
Journal of neuro-oncology  2010;99(1):33-40.
Invasion is a hallmark of malignant gliomas and is the main reason for therapeutic failure and recurrence of the tumor. CXCR4 is a key chemokine receptor implicated in glioma cell migration and whose expression is regulated by hypoxia. Here, we report that, hepatocyte growth factor (HGF) upregulated CXCR4 protein expression in glioma cells. HGF pre-treatment increased migration of U87MG and LN229 glioma cells towards the CXCR4 ligand, stromal cell-derived factor-1α (SDF-1α). AMD3100, a CXCR4 inhibitor, inhibited the increased migration of HGF pre-treated LN229 glioma cells towards SDF-1α. Following exposure to HGF and hypoxia both cell lines showed nuclear translocation of NF-κB (p65). The HGF- and hypoxia-induced nuclear translocation of NF-κB (p65) involved phosphorylation and degradation of IκB-α. Knock-down of NF-κB expression inhibited the induction of CXCR4 expression in response to HGF, but not to hypoxia. However, knock-down of NF-κB expression inhibited the induction of CXCR4 expression in response to hypoxia in the presence of HGF. NF-κB mediated migration towards SDF-1α in response to HGF. Knock-down of NF-κB expression resulted in decreased migration of HGF pre-treated glioma cells towards SDF-1α. Therefore, HGF upregulates CXCR4 expression via NF-κB and leads to enhanced migration. To our knowledge, this is the first report to show that a crosstalk mediated by NF-κB exists between the SDF-1α/CXCR4 and HGF/c-Met axes relevant to glioma cell migration. These findings imply that effective inhibition of glioma invasion should be directed against several ligand/receptor signaling pathways.
doi:10.1007/s11060-010-0111-2
PMCID: PMC3767998  PMID: 20157762
CXCR4; glioma; hepatocyte growth factor; hypoxia; migration; NF-κB
5.  Radiotherapy Enhances Antitumor Effect of Anti-CD137 Therapy in a Mouse Glioma Model 
Radiation research  2010;173(4):426-432.
Previously, we reported that peripheral vaccination of mice with modified autologous tumor cells secreting granulocyte-macrophage colony-stimulating factor (GM-CSF) combined with ionizing radiation to the whole brain cured 50% of mice using a syngeneic, intracranial model of murine high-grade glioma. Here, we tested the combination of radiotherapy (4 Gy × 2) with an immunotherapeutic approach using an anti-CD137 antibody directed to the co-stimulatory molecule CD137. The CD137 antibody has shown promise in generating effective antitumor responses in several animal models and has demonstrated a favorable toxicity profile in the clinic. The combination of radiation and anti-CD137 therapy resulted in complete tumor eradication and prolonged survival in six of nine (67%) mice with established brain tumors (P = 0.0009). Five of six (83%) long-term survivors in the combination group demonstrated antitumor immunity by rejecting challenge tumors. Antitumor immunity was associated with an increased number of tumor-infiltrating lymphocytes (TILs) in brain tumors and increased tumor-specific production of γ IFN. In view of the finding that radiation enhanced the antitumor effect of anti-CD137 therapy, this approach should be studied further for clinical translation.
doi:10.1667/RR1904.1
PMCID: PMC3721320  PMID: 20334514
6.  Flavopiridol downregulates hypoxia-mediated hypoxia-inducible factor-1α expression in human glioma cells by a proteasome-independent pathway: Implications for in vivo therapy1 
Neuro-Oncology  2005;7(3):225-235.
Angiogenesis is a critical step required for sustained tumor growth and tumor progression. The stimulation of endothelial cells by cytokines secreted by tumor cells such as vascular endothelial growth factor (VEGF) induces their proliferation and migration. This is a prominent feature of high-grade gliomas. The secretion of VEGF is greatly upregulated under conditions of hypoxia because of the transcription factor hypoxia-inducible factor (HIF)-1α, which controls the expression of many genes, allowing rapid adaptation of cells to their hypoxic microenvironment. Flavopiridol, a novel cyclin-dependent kinase inhibitor, has been attributed with antiangiogenic properties in some cancer cell lines by its ability to inhibit VEGF production. Here, we show that flavopiridol treatment of human U87MG and T98G glioma cell lines decreases hypoxia-mediated HIF-1α expression, VEGF secretion, and tumor cell migration. These in vitro results correlate with reduced vascularity of intracranial syngeneic GL261 gliomas from animals treated with flavopiridol. In addition, we show that flavopiridol downregulates HIF-1α expression in the presence of a proteasome inhibitor, an agent that normally results in the accumulation and overexpression of HIF-1α. The potential to downregulate HIF-1α expression with flavopiridol treatment in combination with a proteasome inhibitor makes this an extremely attractive anticancer treatment strategy for tumors with high angiogenic activity, such as gliomas.
doi:10.1215/S1152851704000997
PMCID: PMC1871916  PMID: 16053697
flavopiridol; proteasome inhibitor; hypoxia; HIF-1α; VEGF; glioma
7.  Therapeutic Targets in Malignant Glioblastoma Microenvironment 
Seminars in radiation oncology  2009;19(3):163-170.
There is considerable evidence that the tissue microenvironment can suppress cancer, and that microenvironment disruption is required for cancer growth and progression. Distortion of the microenvironment by tumor cells can promote growth, recruit nonmalignant cells that provide physiological resources, and facilitate invasion. Compared to the variable routes taken by cells to become cancers, the response of normal tissue to cancer is relatively consistent such that controlling cancer may be more readily achieved indirectly via the microenvironment. Here, we discuss three ideas about how the microenvironment, consisting of a vasculature, inflammatory cells, immune cells, growth factors and extracellular matrix, might provide therapeutic targets in glioblastoma (GBM) in the context of radiotherapy (RT). First, that viable therapeutic targets exist in the GBM microenvironment; second, that RT alters the microenvironment of tissues and tumors; and third, that potential benefit may be achieved by targeting the microenvironments induced by RT.
doi:10.1016/j.semradonc.2009.02.004
PMCID: PMC3538148  PMID: 19464631
8.  Overexpression and activation of epidermal growth factor receptor in hemangioblastomas 
Journal of neuro-oncology  2010;99(2):195-200.
Hemangioblastomas frequently develop in patients with von Hippel-Lindau (VHL) disease, an autosomal dominant genetic disorder. The tumors are characterized by a dense network of blood capillaries, often in association with cysts. Although activation of receptor tyrosine kinase (RTK) signaling, including epidermal growth factor receptor (EGFR) has been implicated in the development of malignant brain tumors such as high-grade gliomas, little is known about the role of RTK signaling in hemangioblastomas. To address this issue, we examined hemangioblastoma tumor specimens using receptor tyrosine kinase (RTK) activation profiling and immunohistochemistry. Six human hemangioblastomas were analyzed with a phospho-RTK antibody array, revealing EGFR phosphorylation in all tumors. EGFR expression was confirmed by immunohistochemistry in all tumors analyzed and downstream effector pathway activation was demonstrated by positive staining for phospho-AKT. Our findings suggest that, in primary hemangioblastomas, RTK upregulation and signaling predominantly involves EGFR, providing an attractive molecular target for therapeutic intervention.
doi:10.1007/s11060-010-0125-9
PMCID: PMC2928155  PMID: 20730556
Hemangioblastoma; EGFR; Receptor tyrosine kinases; Overexpression
9.  Knock down of HIF-1α in glioma cells reduces migration in vitro and invasion in vivo and impairs their ability to form tumor spheres 
Molecular Cancer  2010;9:133.
Background
Glioblastoma (GBM) is the most common and malignant primary intracranial human neoplasm. GBMs are characterized by the presence of extensive areas of necrosis and hypoxia. Hypoxia and its master regulator, hypoxia inducible factor 1 (HIF-1) play a key role in glioma invasion.
Results
To further elucidate the functional role of HIF-1α in glioma cell migration in vitro and in invasion in vivo, we used a shRNA approach to knock down HIF-1α expression complemented with genome-wide expression profiling, performed in both normoxic and hypoxic conditions. Our data show that knock down of HIF-1α in glioma cells significantly impairs their migration in vitro as well as their ability to invade into the brain parenchyma in vivo. Next, we assessed the role that HIF-1α plays in maintaining the characteristics of cancer stem cells (CSCs). By using the tumor sphere forming assay, we demonstrate that HIF-1α plays a role in the survival and self-renewal potential of CSCs. Finally, expression profiling experiments in glioma cells provided detailed insight into a broad range of specific biological pathways and processes downstream of HIF-1α. We discuss the role of these processes in the migratory and invasive properties, as well as the stem cell biology of glioblastomas
Conclusions
Our data show that knock down of HIF-1α in human and murine glioma cells impairs their migration in vitro and their invasion in vivo. In addition, our data suggest that HIF-1α plays a role in the survival and self-renewal potential of CSCs and identify genes that might further elucidate the role of HIF-1α in tumor migration, invasion and stem cell biology.
doi:10.1186/1476-4598-9-133
PMCID: PMC2896954  PMID: 20515450
10.  Immunotherapy of pediatric brain tumor patients should include an immunoprevention strategy: a medical hypothesis paper 
Journal of Neuro-Oncology  2009;97(2):159-169.
Adults diagnosed with Glioblastoma multiforme (GBM) are frequently faced with a 7% chance of surviving 2 years compared with pediatric patients with GBM who have a 26% survival rate. Our recent screen of possible glioma-associated antigen precursor protein (TAPP) profiles displayed from different types of pediatric brain tumors showed that pediatric patients contained a subset of the tumor antigens displayed by adult GBM patients. Adult GBM possess at least 27 tumor antigens that can potentially stimulate T cell immune responses, suggesting that these tumors are quite antigenic. In contrast, pediatric brain tumors only expressed nine tumor antigens with mRNA levels that were equivalent to those displayed by adult GBM. These tumor-associated antigens could be used as possible targets of therapeutic immunization for pediatric brain cancer patients. Children have developing immune systems that peak at puberty. An immune response mounted by these pediatric patients might account for their extended life spans, even though the pediatric brain tumors express far fewer total tumor-associated antigens. Here we present a hypothesis that pediatric brain tumor patients might be the best patients to show that immunotherapy can be used to successfully treat established cancers. We speculate that immunotherapy should include a panel of tumor antigens that might prevent the out-growth of more malignant tumor cells and thereby prevent the brain tumor relapse. Thus, pediatric brain tumor patients might provide an opportunity to prove the concept of immunoprevention.
doi:10.1007/s11060-009-0016-0
PMCID: PMC2837156  PMID: 19802719
Tumor antigens; Immunotherapy; Glioblastoma multiforme; Fibrillary astrocytoma; Pilocytic astrocytoma; Ependymoma

Results 1-10 (10)