Adrian Merlo

Universität Basel, Bâle, Basel-City, Switzerland

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Publications (79)390.95 Total impact

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    ABSTRACT: Standard treatment of meningiomas consists of surgery and/or radiotherapy. Complex, especially recurrent or progressive cases, may exhibit tumor growth involving critical neurovascular structures or diffuse growth, resulting in limited efficacy and higher risks of standard treatment. We evaluated, if somatostatin receptor-targeted radionuclide therapy with (90)Y-DOTATOC may be a therapeutic option. 15 patients with recurrent or progressive meningiomas after multimodal pretreatment and/or unfavorable medical risk profile were treated with intravenous (90)Y-DOTATOC. Endpoints were progression free survival and toxicity. Usually applied doses were 7400 MBq/m2 (90)Y-DOTATOC in two fractions. Mean observation time was 49.7 months (range 12-137). Median progression free survival was 24 months (mean 44.7, SD 37.8). Toxicity was moderate, mostly hematological (n = 8) and transient. (90)Y-DOTATOC may represent an option for complex recurrent, progressive or diffuse meningiomas. Further studies are needed to evaluate efficacy, long term results and adequate doses for benign and malignant meningiomas. Copyright © 2015 by the Society of Nuclear Medicine and Molecular Imaging, Inc.
    No preview · Article · Aug 2015 · Journal of Nuclear Medicine
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    ABSTRACT: High levels of mammalian target of rapamycin complex 1 (mTORC1) activity in malignant gliomas promote tumor progression, suggesting that targeting mTORC1 has potential as a therapeutic strategy. Remarkably, clinical trials in patients with glioma revealed that rapamycin analogs (rapalogs) have limited efficacy, indicating activation of resistance mechanisms. Targeted depletion of MAPK-interacting Ser/Thr kinase 1 (MNK1) sensitizes glioma cells to the mTORC1 inhibitor rapamycin through an indistinct mechanism. Here, we analyzed how MNK1 and mTORC1 signaling pathways regulate the assembly of translation initiation complexes, using the cap analog m7GTP to enrich for initiation complexes in glioma cells followed by mass spectrometry-based quantitative proteomics. Association of eukaryotic translation initiation factor 4E (eIF4E) with eIF4E-binding protein 1 (4EBP1) was regulated by the mTORC1 pathway, whereas pharmacological blocking of MNK activity by CGP57380 or MNK1 knockdown, along with mTORC1 inhibition by RAD001, increased 4EBP1 binding to eIF4E. Furthermore, combined MNK1 and mTORC1 inhibition profoundly inhibited 4EBP1 phosphorylation at Ser65, protein synthesis and proliferation in glioma cells, and reduced tumor growth in an orthotopic glioblastoma (GBM) mouse model. Immunohistochemical analysis of GBM samples revealed increased 4EBP1 phosphorylation. Taken together, our data indicate that rapalog-activated MNK1 signaling promotes glioma growth through regulation of 4EBP1 and indicate a molecular cross-talk between the mTORC1 and MNK1 pathways that has potential to be exploited therapeutically.
    Preview · Article · Jan 2014 · The Journal of clinical investigation
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    ABSTRACT: Amplification and rearrangements of the epidermal growth factor receptor (EGFR) gene are frequently found in glioblastoma multiforme (GBM). The most common variant is EGFR variant III (EGFRvIII). Research suggests that EGFRvIII could be a marker for a cancer stem cell or tumor-initiating population. If amplification and rearrangement are early events in tumorigenesis, this implies that they should be preserved throughout the tumor. However, in primary GBM, EGFRvIII expression is focal and sporadic. Unexpectedly, we found EGFR amplification and rearrangement throughout the tumor, including regions with no EGFRvIII expression, suggesting that mechanisms exist to modulate EGFRvIII expression even in the presence of high gene amplification. To study this phenomenon, we characterized three GBM cell lines with endogenous EGFRvIII. EGFRvIII expression was heterogeneous, with both positive and negative populations maintaining the genetic alterations, akin to primary tumors. Furthermore, EGFRvIII defined a hierarchy where EGFRvIII-positive cells gave rise to additional positive and negative cells. Only cells that had recently lost EGFRvIII expression could re-express EGFRvIII, providing an important buffer for maintaining EGFRvIII-positive cell numbers. Epigenetic mechanisms had a role in maintaining heterogeneous EGFRvIII expression. Demethylation induced a 20-60% increase in the percentage of EGFRvIII-positive cells, indicating that some cells could re-express EGFRvIII. Surprisingly, inhibition of histone deacetylation resulted in a 50-80% reduction in EGFRvIII expression. Collectively, this data demonstrates that EGFR amplification and rearrangement are early events in tumorigenesis and EGFRvIII follows a model of hierarchical expression. Furthermore, EGFRvIII expression is restricted by epigenetic mechanisms, suggesting that drugs that modulate the epigenome might be used successfully in glioblastoma tumors.
    Full-text · Article · May 2013 · Oncogene
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    ABSTRACT: (GBM) is a highly malignant primary tumor of the central nervous system originating in glial cells. GBM results in more years of life lost than any other cancer type. Low levels of Notch receptor expression correlates with prolonged survival in various high grade gliomas independent of other markers. Different downstream pathways of Notch receptors have been identified. We tested if the Notch/Deltex pathway, which is distinct from the canonical, CSL-mediated pathway, has a role in GBM. We show that the alternative or non-canonical Notch pathway functioning through Deltex1 (DTX1) mediates key features of glioblastoma cell aggressiveness. For example, DTX1 activates the RTK/PI3K/PKB and the MAPK/ERK mitotic pathways and induces anti-apoptotic Mcl-1. The clonogenic and growth potential of established glioma cells correlated with DTX1 levels. Microarray gene expression analysis further identified a DTX1-specific, MAML1-independent transcriptional program - including - which is functionally linked to the changes in tumor cell aggressiveness. Over-expression of DTX1 increased cell migration and invasion correlating to ERK activation, miR-21 levels and endogenous Notch levels. In contrast to high and intermediate expressors, patients with low levels have a more favorable prognosis. The alternative Notch pathway via DTX1 appears to be an oncogenic factor in glioblastoma and these findings offer new potential therapeutic targets.
    Full-text · Article · Feb 2013 · PLoS ONE

  • No preview · Article · Jun 2012 · Cancer Research
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    ABSTRACT: Glioblastoma multiforme (GBM) is the most common and deadly primary brain tumor. Amplification and rearrangements of the epidermal growth factor receptor (EGFR) gene are frequently found in GBM. The most common variant is EGFRvIII, an exon 2-7 deletion mutant resulting from amplification and rearrangement of the EGFR locus. We have hypothesized that EGFRvIII could mark a cancer stem cell or tumor initiating cell population. If amplification and rearrangement are early events in tumorigenesis, this implies that they should be preserved throughout the tumor. However, in primary GBM EGFRvIII expression was focal and sporadic. To understand the relationship between EGFRvIII expression and the underlying genomic alterations, we utilized manual dissection to separate EGFRvIII positive and negative cells and a quantitative PCR assay that detects independently both EGFR amplification and rearrangement. Unexpectedly, we found EGFR amplification and rearrangement throughout the tumor, including regions with no EGFRvIII expression. This supports our hypothesis and further suggests that mechanisms exist to modulate EGFRvIII expression even in the presence of high gene amplification. To study this phenomenon, we characterized three GBM cell lines with endogenous EGFRvIII expression and corresponding EGFR amplification and rearrangement, confirmed by Western blot, RT-PCR and FISH. By flow cytometry analysis EGFRvIII expression was heterogeneous, with 9-50% EGFRvIII positive cells in each cell line. Both positive and negative populations maintained the genetic alterations, recapitulating what we observed in primary GBM. Importantly, EGFRvIII defined a hierarchy where EGFRvIII-positive cells gave rise to additional positive and negative cells. However, only cells that had recently lost EGFRvIII expression could re-express EGFRvIII. Epigenetic mechanisms played a role in modulating EGFRvIII expression to maintain a heterogeneous population. Demethylation induced a 20-60% increase in the percentage of EGFRvIII-positive cells, indicating that some cells could re-express EGFRvIII. Surprisingly, inhibition of histone deacetylation resulted in a 50-80% reduction in EGFRvIII expression. Collectively, this data demonstrates that EGFRvIII does follow a stem cell model for hierarchical expression and sheds light on the existence of a transient population that is able to re-express EGFRvIII, an important buffer for maintaining EGFRvIII-positive cell numbers. Furthermore, we provide the first evidence that EGFRvIII expression can be silenced by epigenetic mechanisms, suggesting that drugs which modulate the epigenome might be used successfully in glioblastoma tumors.
    No preview · Article · Jun 2012 · Cancer Research
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    ABSTRACT: Recent studies identified a highly tumorigenic subpopulation of glioma stem cells (GSCs) within malignant gliomas. GSCs are proposed to originate from transformed neural stem cells (NSCs). Several pathways active in NSCs, including the Notch pathway, were shown to promote proliferation and tumorigenesis in GSCs. Notch2 is highly expressed in glioblastoma multiforme (GBM), a highly malignant astrocytoma. It is therefore conceivable that increased Notch2 signaling in NSCs contributes to the formation of GBM. Here, we demonstrate that mice constitutively expressing the activated intracellular domain of Notch2 in NSCs display a hyperplasia of the neurogenic niche and reduced neuronal lineage entry. Neurospheres derived from these mice show increased proliferation, survival and resistance to apoptosis. Moreover, they preferentially differentiate into astrocytes, which are the characteristic cellular population of astrocytoma. Likewise, we show that Notch2 signaling increases proliferation and resistance to apoptosis in human GBM cell lines. Gene expression profiling of GBM patient tumor samples reveals a positive correlation of Notch2 transcripts with gene transcripts controlling anti-apoptotic processes, stemness and astrocyte fate, and a negative correlation with gene transcripts controlling proapoptotic processes and oligodendrocyte fate. Our data show that Notch2 signaling in NSCs produces features of GSCs and induces astrocytic lineage entry, consistent with a possible role in astrocytoma formation.
    Full-text · Article · Jun 2012 · Cell Death & Disease
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    ABSTRACT: The infiltration of glioma cells into adjacent tissue is one of the major obstacles in the therapeutic management of malignant brain tumours, in most cases precluding complete surgical resection. Consequently, malignant glioma patients almost invariably experience tumour recurrences. Within the brain, glioma cells migrate rapidly either amoeboidly or mesenchymally to invade surrounding structures, in dependence on the extracellular environment. In addition, radiotherapy, frequently applied as adjuvant therapeutic modality, may enhance tumour cell mobility. Here, we show that the receptor tyrosine kinase Mer (MerTK) is overexpressed in glioblastoma multiforme (GBM) and that this is accompanied with increased invasive potential. MerTK expression is maintained in primary GBM-derived tumour spheres under stem cell culture conditions but diminishes significantly in serum-containing cultures with concomitant downregulation of Nestin and Sox2. Depletion of MerTK disrupts the rounded morphology of glioma cells and decreases their invasive capacity. Furthermore, the expression and phosphorylation of myosin light chain 2 are strongly associated with MerTK activity, indicating that the effect of MerTK on glioma cell invasion is mediated by actomyosin contractility. Finally, DNA damage robustly triggers the upregulation and phosphorylation of MerTK, which protects cells from apoptosis. This effect is strongly impaired upon MerTK depletion or overexpression of an inactive MerTK mutant. Collectively, our data suggests that MerTK is a novel therapeutic target in the treatment of the malignant gliomas.Oncogene advance online publication, 2 April 2012; doi:10.1038/onc.2012.104.
    Preview · Article · Apr 2012 · Oncogene
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    Roland M Huber · Adrian Merlo · Brian A Hemmings
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    ABSTRACT: Kinases relay incoming input to downstream proteins by covalently linking phosphate groups to their targets. This phosphorylation acts as a biological switch regulating the func-tion of the target molecules. While simple in its general design, protein kinase signaling functions in highly complex networks and cascades regulating some of the most essential cel-lular and physiological functions. Subtle changes in these networks can have devastating consequences and the deadliest among all is cancer. Primary brain tumors of glial origin show mutations and alterations in several kinase cascades leading to aberrant growth and tissue invasion. Molecular profiling has identified key pathways of gliomagenesis but due to the redundancy among glioma promoting signaling pathways, highly specific kinase inhibi-tors used in mono-therapies have not led to clear clinical benefits so far. Adding to the dis-mal prognosis of glioma patients is the strong angiogenic potential of these tumors; again, a process with a kinase as key regulator which is targeted by several molecular strategies. In this review, we summarize the kinases involved in the main features of glioblastoma, the ef-fect targeted therapies against these kinases have shown so far and critically discuss future options of targeting kinases in glioma therapy.
    Preview · Article · Feb 2012 · Biomedical Research
  • Serdar Korur · Maria Maddalena Lino · Adrian Merlo
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    ABSTRACT: Neural stem cells and progenitor cells have been discovered in multiple regions of the brain. These progenitor cells, in addition to differentiated glia, may constitute a substrate for neoplastic transformation. In recent years, it had been suggested that only a subset of cells in a cancer, the so-called cancer stem cells (CSCs), are endowed with tumorigenic capacity. These are self-renewing and multipotent cells with tumor-initiating potential. Few of these CSCs are able to reproduce the original tumor in vivo. The alternative hypothesis that transformation and de-differentiation of more mature brain cells contributes to tumorigenesis may be a parallel pathway towards tumorigenesis. Malignant brain tumors are amongst the deadliest human cancers, and effective therapy has not emerged up to now. CSC in brain tumors are regulated by different factors, e.g., Notch, GSK3, BMI1, SHH, SOX, musashi. This review summarizes studies on brain tumor precursor cells, their molecular signature, and emerging new approaches for therapeutic targeting.
    No preview · Chapter · Oct 2011
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    ABSTRACT: Amplification of the epidermal growth factor receptor (EGFR) gene is one of the most common oncogenic alterations in glioblastoma (45%) making it a prime target for therapy. However, small molecule inhibitors of the EGFR tyrosine kinase showed disappointing efficacy in clinical trials for glioblastoma. Here we aimed at investigating the molecular effects of the tyrosine kinase inhibitor gefitinib on the EGFR signaling pathway in human glioblastoma. Twenty-two patients selected for reoperation of recurrent glioblastoma were treated within a phase II trial for 5 days with 500 mg gefitinib before surgery followed by postoperative gefitinib until recurrence. Resected glioblastoma tissues exhibited high concentrations of gefitinib (median, 4.1 μg/g), 20 times higher than respective plasma. EGFR-pathway activity was evaluated with phosphorylation-specific assays. The EGFR was efficiently dephosphorylated in treated patients as compared to a control cohort of 12 patients. However, no significant effect on 12 pathway constituents was detected. In contrast, in vitro treatment of a glioblastoma cell line, BS-153, with endogenous EGFRwt amplification and EGFRvIII expression resulted not only in dephosphorylation of the EGFR, but also of key regulators in the pathway such as AKT. Treating established xenografts of the same cell line as an in vivo model showed dephosphorylation of the EGFR without affecting downstream signal transductors, similar to the human glioblastoma. Taken together, gefitinib reaches high concentrations in the tumor tissue and efficiently dephosphorylates its target. However, regulation of downstream signal transducers in the EGFR pathway seems to be dominated by regulatory circuits independent of EGFR phosphorylation.
    Full-text · Article · Apr 2011 · Molecular Cancer Therapeutics
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    ABSTRACT: Glioblastoma multiforme (GBM) is the most common aggressive brain cancer with a median survival of approximately 1 year. In a search for novel molecular targets that could be therapeutically developed, our kinome-focused microarray analysis identified the MAP (mitogen-activated protein) kinase-interacting kinase 1 (MNK1) as an attractive theranostic candidate. MNK1 overexpression was confirmed in both primary GBMs and glioma cell lines. Inhibition of MNK1 activity in GBM cells by the small molecule CGP57380 suppressed eIF4E phosphorylation, proliferation, and colony formation whereas concomitant treatment with CGP57380 and the mTOR inhibitor rapamycin accentuated growth inhibition and cell-cycle arrest. siRNA-mediated knockdown of MNK1 expression reduced proliferation of cells incubated with rapamycin. Conversely, overexpression of full-length MNK1 reduced rapamycin-induced growth inhibition. Analysis of polysomal profiles revealed inhibition of translation in CGP57380 and rapamycin-treated cells. Microarray analysis of total and polysomal RNA from MNK1-depleted GBM cells identified mRNAs involved in regulation of TGF-β pathway. Translation of SMAD2 mRNA as well as TGF-β-induced cell motility and vimentin expression was regulated by MNK1 signaling. Tissue microarray analysis revealed a positive correlation between the immunohistochemical staining of MNK1 and SMAD2. Taken together, our findings offer insights into how MNK1 pathways control translation of cancer-related mRNAs including SMAD2, a key component of the TGF-β signaling pathway. Furthermore, they suggest MNK1-controlled translational pathways in targeted strategies to more effectively treat GBM.
    No preview · Article · Mar 2011 · Cancer Research
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    ABSTRACT: Tenascin-C is an extracellular matrix protein over-expressed in a large variety of cancers. In the present study, we aimed at identifying new interactors of tenascin-C by purifying secreted proteins on a tenascin-C affinity column. Analysis of eluates by mass spectrometry revealed phosphoglycerate kinase 1, clusterin, fibronectin, SPARC-related modular calcium-binding protein 1 (SMOC1) and nidogen-2 as potential interactors of tenascin-C. The interaction between tenascin-C and SMOC1 was confirmed by co-immunoprecipitation and further analyzed by Surface Plasmon Resonance Spectroscopy, which revealed an apparent dissociation constant (K(D)) value of 2.59∗10(-9)M. Further analyses showed that this binding is reduced in the presence of EDTA. To investigate whether SMOC1 itself could be over-expressed in the context of tumorigenesis, we analyzed data of two independent RNA profiling studies and found that mRNA levels of SMOC1 are significantly increased in oligodendrogliomas compared to control brain samples. In support of these data, western blot analysis of protein extracts from 12 oligodendrogliomas, 4 astrocytomas and 13 glioblastomas revealed elevated levels compared to healthy brain extract. Interestingly, cell migration experiments revealed that SMOC1 can counteract the chemo-attractive effect of tenascin-C on U87 glioma cells. The present study thus identified SMOC1 as a new cancer-associated protein capable of interacting with tenascin-C in vitro.
    No preview · Article · Feb 2011 · Matrix biology: journal of the International Society for Matrix Biology
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    ABSTRACT: Malignant gliomas are among the most devastating tumors for which conventional therapies have not significantly improved patient outcome. Despite advances in imaging, surgery, chemotherapy and radiotherapy, survival is still less than 2 years from diagnosis and more targeted therapies are urgently needed. Notch signaling is central to the normal and neoplastic development of the central nervous system, playing important roles in proliferation, differentiation, apoptosis and cancer stem cell regulation. Notch is also involved in the regulation response to hypoxia and angiogenesis, which are typical tumor and more specifically glioblastoma multiforme (GBM) features. Targeting Notch signaling is therefore a promising strategy for developing future therapies for the treatment of GBM. In this review we give an overview of the mechanisms of Notch signaling, its networking pathways in gliomas, and discuss its potential for designing novel therapeutic approaches.
    Preview · Article · Nov 2010 · BMC Medicine
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    M.M. Lino · A Merlo
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    ABSTRACT: Glioblastoma (GBM) is the most common primary tumor of the CNS in the adult. It is characterized by exponential growth and diffuse invasiveness. Among many different genetic alterations in GBM, e.g., mutations of PTEN, EGFR, p16/p19 and p53 and their impact on aberrant signaling have been thoroughly characterized. A major barrier to develop a common therapeutic strategy is founded on the fact that each tumor has its individual genetic fingerprint. Nonetheless, the PI3K pathway may represent a common therapeutic target to most GBM due to its central position in the signaling cascade affecting proliferation, apoptosis and migration. The read-out of blocking PI3K alone or in combination with other cancer pathways should mainly focus, besides the cytostatic effect, on cell death induction since sublethal damage may induce selection of more malignant clones. Targeting more than one pathway instead of a single agent approach may be more promising to kill GBM cells.
    Preview · Article · Nov 2010 · Journal of Neuro-Oncology
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    ABSTRACT: Spontaneous intracerebral hemorrhage (ICH) accounts for a high mortality and morbidity. Early prediction of outcome is crucial for optimized care and treatment decision. Copeptin, the C-terminal part of provasopressin, has emerged as a new prognostic marker in a variety of diseases, but its prognostic value in ICH is unknown. In 40 consecutive patients who were admitted to the hospital within 72 hours after a spontaneous ICH, the plasma copeptin level was measured with a sandwich immunoassay upon admission. The prognostic value of copeptin to predict 30 day mortality and functional outcome after 90 days was assessed. A favorable outcome was defined as a Barthel score above 85 and a score below 3 on the Modified Rankin Scale. Copeptin correlated positively with hematoma volume (r = 0.32, p < 0.05) and negatively with the Glasgow Coma Scale (GCS) on admission (r = -0.35, p < 0.05). Copeptin levels were higher in patients who died within 30 days than in 30-day survivors (179.0 pmol/l (IQR 33.7- 566.0) vs. 12.9 pmol/l (IQR 5.2 - 42.8), p = 0.003). Copeptin levels were also higher in patients with an unfavorable functional outcome at 90 days compared to patients with a favorable outcome (32.4 pmol/l (IQR 9.5-97.8) vs. 11.9 pmol/l (IQR 3.2-19.8), p = 0.04). For the prediction of death, receiver-operating-characteristics analysis revealed an area under the curve (AUC) for copeptin of 0.88 (95%CI 0.75-1.00). The predictive value of the copeptin concentration was thus similar to that of GCS (AUC 0.82 (95%CI 0.59-1.00) p = 0.53), of the ICH Score (AUC 0.89, (95%CI 0.76-1.00), p = 0.94) and the ICH Grading Scale (AUC 0.86 (95%CI 0.69-1.00), p = 0.81). Copeptin is a new prognostic marker in patients with an ICH. If this finding can be confirmed in larger studies, copeptin might be an additional valuable tool for risk stratification and decision-making in the acute phase of ICH.
    Full-text · Article · May 2010 · BMC Neurology
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    ABSTRACT: Complete surgical resection beyond tumor margins cannot be achieved in glioblastoma multiforme (GBM) because of infiltrative nature. In several cancers, neoadjuvant treatment has been implemented to reduce the risk of tumor cell spreading during resection. In GBM, the objective of a neoadjuvant approach is reduction of tumor cells within the main tumor mass and beyond in the infiltration zone. Such an approach can only be performed if elevated intracranial pressure can be medically controlled. In a previous study with recurrent gliomas, we showed that local intratumoral injection of radiolabeled DOTAGA-substance P substantially inhibited further growth and led to radionecrotic transformation of the tumor (CCR 2006). We have now examined this modality as neoadjuvant treatment for GBM, primarily assessing feasibility, toxicity, the extent of resection, and functional outcome. After diagnosis of GBM, 17 patients were included in a prospective phase I study. Repetitive intratumoral injections of radiolabeled DOTAGA-substance P were performed, followed by surgical resection. Chemical synthesis, radiolabeling, and local injection of the peptidic vector [90Yttrium]-DOTAGA-substance P were described previously. Neoadjuvant injection of [90Y]-DOTAGA-substance P was feasible without decompensation of intracranial pressure. Prolonged application of corticosteroids was identified as the main risk factor for side effects. Fifteen patients stabilized or improved their functional status. The mean extent of resection in subsequent surgery was 96%. Neoadjuvant therapy of GBM using locally injected radiolabeled DOTAGA-substance P was feasible and of low toxicity. The high extent of resection and concomitant irradiation of tumor cells in the infiltration zone may be prognostically relevant.
    No preview · Article · Mar 2010 · Journal of Neuro-Oncology
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    ABSTRACT: Functionally critically located gliomas represent a challenging subgroup of intrinsic brain neoplasms. Standard therapeutic recommendations often cannot be applied, because radical treatment and preservation of neurological function are contrary goals. The successful targeting of gliomas with locally injected beta radiation-emitting (90)Y-DOTAGA-substance P has been shown previously. However, in critically located tumours, the mean tissue range of 5 mm of (90)Y may seriously damage adjacent brain areas. In contrast, the alpha radiation-emitting radionuclide (213)Bi with a mean tissue range of 81 microm may have a more favourable toxicity profile. Therefore, we evaluated locally injected (213)Bi-DOTA-substance P in patients with critically located gliomas as the primary therapeutic modality. In a pilot study, we included five patients with critically located gliomas (WHO grades II-IV). After diagnosis by biopsy, (213)Bi-DOTA-substance P was locally injected, followed by serial SPECT/CT and MR imaging and blood sampling. Besides feasibility and toxicity, the functional outcome was evaluated. Targeted radiopeptide therapy using (213)Bi-DOTA-substance P was feasible and tolerated without additional neurological deficit. No local or systemic toxicity was observed. (213)Bi-DOTA-substance P showed high retention at the target site. MR imaging was suggestive of radiation-induced necrosis and demarcation of the tumours, which was validated by subsequent resection. This study provides proof of concept that targeted local radiotherapy using (213)Bi-DOTA-substance P is feasible and may represent an innovative and effective treatment for critically located gliomas. Primarily non-operable gliomas may become resectable with this treatment, thereby possibly improving the prognosis.
    No preview · Article · Feb 2010 · European Journal of Nuclear Medicine
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    ABSTRACT: The microenvironment hosting a tumor actively participates in regulating tumor cell proliferation, migration, and invasion. Among the extracellular matrix proteins enriched in the stroma of carcinomas are the tenascin family members tenascin-C and tenascin-W. Whereas tenascin-C overexpression in gliomas is known to correlate with poor prognosis, the status of tenascin-W in brain tumors has not been investigated so far. In the present study, we analyzed protein levels of tenascin-W in 38 human gliomas and found expression of tenascin-W in 80% of the tumor samples, whereas no tenascin-W could be detected in control, nontumoral brain tissues. Double immunohistochemical staining of tenascin-W and von Willebrand factor revealed that tenascin-W is localized around blood vessels, exclusively in tumor samples. In vitro, the presence of tenascin-W increased the proportion of elongated human umbilical vein endothelial cells (HUVECs) and augmented the mean speed of cell migration. Furthermore, tenascin-W triggered sprouting of HUVEC spheroids to a similar extent as the proangiogenic factor tenascin-C. In conclusion, our study identifies tenascin-W as a candidate biomarker for brain tumor angiogenesis that could be used as a molecular target for therapy irrespective of the glioma subtype.-Martina, E., Degen, M., Rüegg, C., Merlo, A., Lino, M. M., Chiquet-Ehrismann, R., Brellier, F. Tenascin-W is a specific marker of glioma-associated blood vessels and stimulates angiogenesis in vitro.
    No preview · Article · Nov 2009 · The FASEB Journal
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    ABSTRACT: Loss of heterozygosity (LOH) of the entire chromosome 10 is the most frequent genetic alteration in human glioblastoma (GBM). In addition to PTEN/MMAC1 on 10q23.3, clustering of partial deletion break-points on 10q25.3-26.1 points to a second suppressor locus. The proposed target gene DMBT1 was not confirmed. By somatic deletion mapping of this region, we identified the complementary DNA encoding the human homologue of rat orphan G protein-coupled receptor GPR26. GPR26 is highly expressed in fetal and adult brain, but frequently reduced or absent in glioma cells and biopsies, due to de novo methylation of its 5' CpG island. Silencing of GPR26 was reversed with 5-aza-deoxycytidine and the histone deacetylase inhibitor trichostatin A. Furthermore, overexpression of GPR26 in HEK and in U87 glioma cells increased intracellular cAMP concentration which is considered to induce astrocytic differentiation. Interestingly, we observed concomitant silencing of GPR26 with O6-methylguanine-DNA methyl transferase (MGMT), a DNA repair gene co-localized on 10q25.3-26.1 (p=0.0001). We conclude that epigenetic silencing is a common mechanism in malignant gliomas that simultaneously inactivates MGMT and GPR26. The 10q25.3-26.1 region may contain an important epigenetic pathway in brain tumorigenesis.
    Preview · Article · Nov 2009 · International Journal of Oncology

Publication Stats

3k Citations
390.95 Total Impact Points

Institutions

  • 1993-2013
    • Universität Basel
      • Department of Chemistry
      Bâle, Basel-City, Switzerland
  • 1997-2011
    • Universitätsspital Basel
      • Neurobiology Unit
      Bâle, Basel-City, Switzerland
  • 2009
    • Friedrich Miescher Institute for Biomedical Research
      Bâle, Basel-City, Switzerland
  • 2002
    • Heinrich-Heine-Universität Düsseldorf
      • Institute of Neuropathology
      Düsseldorf, North Rhine-Westphalia, Germany