Cilengitide is a selective ?v?3 and ?v?5 integrin inhibitor. Data from phase 2 trials suggest that it has antitumour activity as a single agent in recurrent glioblastoma and in combination with standard temozolomide chemoradiotherapy in newly diagnosed glioblastoma (particularly in tumours with methylated MGMT promoter). We aimed to assess cilengitide combined with temozolomide chemoradiotherapy in patients with newly diagnosed glioblastoma with methylated MGMT promoter.
Versican is a large chondroitin sulphate proteoglycan produced by several tumor cell types, including high-grade gliomas. Increased expression of distinct versican isoforms in the extracellular matrix plays a role in tumor cell growth, adhesion and migration. We have recently shown that transforming growth factor (TGF-beta)2, an important modulator of glioma invasion, interacts with versican isoforms V0/V1 during malignant progression of glioma in vitro. However, the distinct subtype of versican that modulates these effects could not be specified. Here, we show that transient down-regulation of V1 by siRNA leads to a significant reduction of proliferation and migration in glioblastoma cell lines and glioblastoma progenitor cells, whereas tumor cell attachment stays unaffected. We conclude that V1 plays a predominant role in modulating central pathophysiological mechanisms as proliferation and migration in glioblastoma. Considering that TGF-beta is a master regulator of glioma pathophysiology, and that V0/1 is induced by TGF-beta2, therapeutic regulation of V1 may induce meaningful effects on glioma cell migration not only in vitro, but also in vivo.
Central nervous system primitive neuroectodermal tumors (CNS-PNET) and pineoblastomas (PBL) are rare in adulthood. Knowledge on clinical outcome and the efficacy and toxicities of chemotherapy in addition to radiotherapy is limited. Patients older than 21 years at diagnosis were followed in the observational arm of the prospective pediatric multicenter trial HIT 2000. After surgery, craniospinal irradiation and maintenance or sandwich chemotherapy were recommended. Radiotherapy was normo- (35.2 Gy; tumor region, 55.0 Gy; metastasis, 49.6 Gy) or hyperfractionated (40.0 Gy; tumor bed, 68.0 Gy; metastasis, 50-60 Gy). Maintenance chemotherapy consisted of eight courses (vincristine, lomustine, cisplatin). Sandwich chemotherapy included two cycles of postoperative chemotherapy followed by radiotherapy, and four courses of maintenance chemotherapy. Seventeen patients (CNS-PNET, n = 7; PBL, n = 10), median age 30 years, were included. Eight patients had a postoperative residual tumor and four patients metastatic disease. The median follow-up of ten surviving patients was 41 months. The estimated rates for 3-year progression-free survival (PFS) and overall survival were 68 ± 12 and 66 ± 13%, respectively. PBL compared to CNS-PNET tended towards a better PFS, although the difference was not clear (p = 0.101). Both chemotherapeutic (maintenance, n = 6; sandwich, n = 8) protocols did not differ in their PFS and were feasible with acceptable toxicities. Intensified regimens of combined chemo- and radiotherapy are generally feasible in adults with CNS-PNET/PBL. The impact of intensified chemotherapy on survival should be further assessed.
High-grade gliomas are amongst the most deadly human tumors. Treatment results are disappointing. Still, in several trials around 20% of patients respond to therapy. To date, diagnostic strategies to identify patients that will profit from a specific therapy do not exist.
In randomised controlled trials (RCTs), patient informed consent documents are an essential cornerstone of the study flow. However, these documents are often oversized in format and content. Clinical experience suggests that study information sheets are often not used as an aid to decision-making due to their complexity.
Individualized therapies are popular current concepts in oncology and first steps towards stratified medicine have now been taken in neurooncology through implementation of stratified therapeutic approaches. Knowledge about the molecular basis of brain tumors has expanded greatly in recent years and a few molecular alterations are studied routinely because of their clinical relevance. However, no single targeted agent has yet been fully approved for the treatment of glial brain tumors. In this review, we argue that multidisciplinary and integrated approaches are essential for translational research and the development of new treatments for patients with malignant gliomas, and we present a conceptual framework in which to place the components of such an interdisciplinary approach. We believe that this ambitious goal can be best realized through strong cooperation of brain tumor centers with local hospitals and physicians; such an approach enables close dialogue between expert subspecialty clinicians and local therapists to consider all aspects of this increasingly complex set of diseases.
Stem cells offer great potential for regenerative medicine because they regenerate damaged tissue by cell replacement and/or by stimulating endogenous repair mechanisms. Although stem cells are defined by their functional properties, such as the potential to proliferate, to self-renew, and to differentiate into specific cell types, their identification based on the expression of specific markers remains vague. Here, profiles of stem cell metabolism might highlight stem cell function more than the expression of single genes/markers. Thus, systematic approaches including spectroscopy might yield insight into stem cell function, identity, and stemness. We review the findings gained by means of metabolic and spectroscopic profiling methodologies, for example, nuclear magnetic resonance spectroscopy (NMRS), mass spectrometry (MS), and Raman spectroscopy (RS), with a focus on neural stem cells and neurogenesis.
An important phenomenon observed in glioma metabolism is increased aerobic glycolysis in tumor cells, which is generally referred to as the Warburg effect. Transforming growth factor (TGF)-beta2, which we previously showed to be induced by lactic acid, is a key pathophysiological factor in glioblastoma, leading to increased invasion and severe local immunosuppression after proteolytic cleavage from its latency associated peptide. In this study we tested the hypothesis, that lactate regulates TGF-beta2 expression and glioma cell migration via induction of Thrombospondin-1 (THBS-1), a TGF-beta activating protein.
An adequately sampled tumor histology that is evaluated by an experienced neuropathologist is the current international standard for the diagnosis of high-grade gliomas. We present the case of a 30-year-old female for whom clinical and radiological information dramatically changed the histological diagnosis. We suggest a new algorithm including these parameters to refine the accuracy of histological diagnosis both for standard treatment and centrally reviewed clinical trials.
Non-steroidal anti-inflammatory drugs such as diclofenac exhibit potent anticancer effects. Up to now these effects were mainly attributed to its classical role as COX-inhibitor. Here we show novel COX-independent effects of diclofenac. Diclofenac significantly diminished MYC expression and modulated glucose metabolism resulting in impaired melanoma, leukemia, and carcinoma cell line proliferation in vitro and reduced melanoma growth in vivo. In contrast, the non-selective COX inhibitor aspirin and the COX-2 specific inhibitor NS-398 had no effect on MYC expression and glucose metabolism. Diclofenac significantly decreased glucose transporter 1 (GLUT1), lactate dehydrogenase A (LDHA), and monocarboxylate transporter 1 (MCT1) gene expression in line with a decrease in glucose uptake and lactate secretion. A significant intracellular accumulation of lactate by diclofenac preceded the observed effect on gene expression, suggesting a direct inhibitory effect of diclofenac on lactate efflux. While intracellular lactate accumulation impairs cellular proliferation and gene expression, it does not inhibit MYC expression as evidenced by the lack of MYC regulation by the MCT inhibitor ?-cyano-4-hydroxycinnamic acid. Finally, in a cell line with a tetracycline-regulated c-MYC gene, diclofenac decreased proliferation both in the presence and absence of c-MYC. Thus, diclofenac targets tumor cell proliferation via two mechanisms, that is inhibition of MYC and lactate transport. Based on these results, diclofenac holds potential as a clinically applicable MYC and glycolysis inhibitor supporting established tumor therapies.
The noninvasive tracking of glioblastoma cancer stem cells (CSCs) in vivo constitutes a prerequisite for the development of CSC-specific therapies. Therefore, as a pilot study to identify CSC biomarkers for clinical magnetic resonance spectroscopy, 10 CSC lines were investigated using high-resolution (1)H-nuclear magnetic resonance ((1)H-NMR) spectroscopy at 600 and 800 MHz (14.4 and 18.8 T) under reproducible in vitro conditions. The spectra were analyzed using principal component analysis (PCA), and spectral regions of high variability were evaluated regarding correlations to stem cell-related properties (clonogenic index and CD133 positivity) and cell death. PCA revealed that duplicates of CSC lines clustered together suggesting a characteristic (1)H-NMR pattern of each CSC line. PCA enabled discrimination between samples with high and low clonogenicity, that is, clustering according to one of the hallmarks of stemness in samples with high viability. High/moderate correlations to clonogenicity and CD133 were found in spectral regions with high variability. In contrast, the mobile lipid signal at 1.28 ppm correlated to cell death, but not to stemness, as published previously for neural progenitor cells. In conclusion, our exploratory study demonstrates the correlation of specific resonances within (1)H-NMR spectra with stem cell properties and advocates the use of the 1.28 ppm resonance as biomarker for cell death also in CSCs.
The objective of this prospective, monocentric phase-II pilot study was to evaluate toxicity and efficacy of neoadjuvant temozolomide (TMZ) and 13-cis retinoic acid (13-cRA) treatment in patients with newly diagnosed anaplastic gliomas after total or subtotal tumor resection. The primary endpoint of the study was median progression-free survival (PFS). Secondary endpoints were toxicity and PFS rates at 6, 12 and 24 months. Thirty-two adult patients were included in the study and treated with a median number of 10 TMZ and 13-cRA cycles (range 1-26). The majority of patients had favorable prognostic factors characterized by young age, complete resection, oligodendroglial histology, 1p/19q co-deletion, O6-methylguanine-DNA methyltransferase (MGMT) promotor methylation and isocitrate dehydrogenase 1 (IDH1) mutation. Grade 3/4 myelotoxicity occurred in 5/32 patients, and about 90% of patients suffered from grade 2/3 adverse events attributable to 13-cRA. The median PFS was 37.8 months (95% CI 22.2-53.4). The 6-, 12- and 24-month PFS rates were 84.4, 75 and 42.4%. The extent of tumor resection was the only prognostic factor associated with better PFS. TMZ and 13-cRA treatment did not improve PFS when retrospectively compared to the TMZ-treated group within the randomized NOA-04 phase-III trial. In conclusion, 13-cRA addition to TMZ in a neoadjuvant setting showed acceptable toxicity, but did not yield an advantage in PFS in patients with newly diagnosed anaplastic gliomas after total or subtotal tumor resection.
High-grade gliomas are the most common primary tumors in the central nervous system (CNS) in adults. Despite efforts to improve treatment by combination therapies (neurosurgery, radio- and chemotherapy), high-grade glioma patients still have a grim prognosis, indicating an urgent need for new therapeutic approaches. The molecular processes of gliomagenesis are being unraveled, and novel targeted therapeutic strategies to defy high-grade gliomas are emerging. Transforming growth factor-beta (TGF-?), in particular the TGF-?2 isoform, has been identified as a key factor in the progression of malignant gliomas. TGF-?2, originally described as "glioblastoma-derived T-cell suppressor factor", is associated with the immuno-suppressed status of patients with glioblastoma, and is therefore responsible for loss of tumor immune surveillance. Elevated TGF-?2 levels in tumors and in the plasma of patients have been associated with advanced disease stage and poor prognosis. Consequently, a targeted strategy to modulate TGF-?2 signaling is highly promising. The antisense oligonucleotide trabedersen (AP 12009) that specifically blocks TGF-?2 mRNA will be the main focus of this review. In three phase I/II studies and a randomized, active-controlled dose-finding phase IIb study, trabedersen treatment of high-grade glioma patients with recurrent or refractory tumor disease led to long-lasting tumor responses and so far promising survival data. On the basis of these data the currently ongoing phase III study SAPHIRRE was initiated.
Imaging techniques are important for accurate diagnosis and follow-up of patients with gliomas. T1-weighted MRI, with or without gadolinium, is the gold standard method. However, this technique only reflects biological activity of the tumour indirectly by detecting the breakdown of the blood-brain barrier. Therefore, especially for low-grade glioma or after treatment, T1-weighted MRI enhanced with gadolinium has substantial limitations. Development of more advanced imaging methods to improve outcomes for individual patients is needed. New imaging methods based on MRI and PET can be employed in various stages of disease to target the biological activity of the tumour cells (eg, increased uptake of aminoacids or nucleoside analogues), the changes in diffusivity through the interstitial space (diffusion-weighted MRI), the tumour-induced neovascularisation (perfusion-weighted MRI or contrast-enhanced MRI, or increased uptake of aminoacids in endothelial wall), and the changes in concentrations of metabolites (magnetic resonance spectroscopy). These techniques have advantages and disadvantages, and should be used in conjunction to best help individual patients. Advanced imaging techniques need to be validated in clinical trials to ensure standardisation and evidence-based implementation in routine clinical practice.
Antisense oligodeoxynucleotides (AS-ODNs) have been widely used to determine gene function, validate drug targets and as novel therapeutics for human diseases. In this review, we describe the development of AS-ODNs, including their modifications, pharmacokinetics and toxicity in animal models and humans, and their preclinical and clinical development in the therapy of human high-grade gliomas. The most advanced AS-ODN for the therapy of high-grade gliomas is a phosphorothioate-modified AS-ODN, AP 12009 (trabedersen), which targets mRNA encoding TGF-beta2. AP 12009 is administered intratumorally using convection-enhanced delivery. A series of Phase I and II clinical trials have evaluated the toxicity profile and optimal dose of the substance. A randomized, controlled international Phase III study was initiated in March 2009 and will compare trabedersen 10 microM versus conventional alkylating chemotherapy in patients with recurrent or refractory anaplastic astrocytoma after standard radio- and chemotherapy.
Lactate dehydrogenase type A (LDH-A) is a key metabolic enzyme catalyzing pyruvate into lactate and is excessively expressed by tumor cells. Transforming growth factor-beta2 (TGF-beta2) is a key regulator of invasion in high-grade gliomas, partially by inducing a mesenchymal phenotype and by remodeling the extracellular matrix. In this study, we tested the hypothesis that lactate metabolism regulates TGF-beta2-mediated migration of glioma cells. Small interfering RNA directed against LDH-A (siLDH-A) suppresses, and lactate induces, TGF-beta2 expression, suggesting that lactate metabolism is strongly associated with TGF-beta2 in glioma cells. Here we demonstrate that TGF-beta2 enhances expression, secretion, and activation of matrix metalloproteinase-2 (MMP-2) and induces the cell surface expression of integrin alpha(v)beta(3) receptors. In spheroid and Boyden chamber migration assays, inhibition of MMP-2 activity using a specific MMP-2 inhibitor and blocking of integrin alpha(v)beta(3) abrogated glioma cell migration stimulated by TGF-beta2. Furthermore, siLDH-A inhibited MMP2 activity, leading to inhibition of glioma migration. Taken together, we define an LDH-A-induced and TGF-beta2-coordinated regulatory cascade of transcriptional regulation of MMP-2 and integrin alpha(v)beta(3). This novel interaction between lactate metabolism and TGF-beta2 might constitute a crucial mechanism for glioma migration.
Glioblastoma is a highly vascularised tumour with a high expression of both vascular endothelial growth factor (VEGF) and VEGFR. PTK787/ZK222584 (PTK/ZK, vatalanib), a multiple VEGF receptor inhibitor, blocks the intracellular tyrosine kinase activity of all known VEGF receptors and is therefore suitable for long-term therapy of pathologic tumour neovascularisation.
A systemic and intraventricular polychemotherapy regimen (the Bonn protocol) without radiotherapy resulted in durable responses in 75% of patients <60 years with primary CNS lymphoma (PCNSL), but was complicated by a high rate of Ommaya reservoir infections. Here, the efficacy and toxicity of this regimen without intraventricular treatment was evaluated in PCNSL.
Non-invasive loco-regional electro-hyperthermia (EHT) plus alkylating chemotherapy is occasionally used as salvage treatment in the relapse of patients with high-grade gliomas. Experimental data and retrospective studies suggest potential effects. However, no prospective clinical results are available. We performed a single-center prospective non-controlled single-arm Phase I trial. Main inclusion criteria were recurrent high-grade glioma WHO Grade III or IV, age 18-70, and Karnofsky performance score > or = 70. Primary endpoints were dose-limiting toxicities (DLT) and maximum tolerated dose (MTD) with the combined regimen. Groups of 3 or 4 patients were treated 2-5 times a week in a dose-escalation scheme with EHT. Alkylating chemotherapy (ACNU, nimustin) was administered at a dose of 90 mg/m(2) on day 1 of 42 days for up to six cycles or until tumor progression (PD) or DLT occurred. Fifteen patients with high-grade gliomas were included. Relevant toxicities were local pain and increased focal neurological signs or intracranial pressure. No DLT occurred. In some patients, the administration of mannitol during EHT or long-term use of corticosteroids was necessary to resolve symptoms. Although some patients showed responses in their primarily treated sites, the pattern of response was not well defined. EHT plus alkylating chemotherapy is tolerable in patients with relapse of high-grade gliomas. Episodes of intracranial pressure were, at least, possibly attributed to EHT but did not cause DLTs. A Phase II trial targeting treatment effects is warranted on the basis of the results raised in this trial.
In 2004, a randomised phase III trial by the European Organisation for Research and Treatment of Cancer (EORTC) and National Cancer Institute of Canada Clinical Trials Group (NCIC) reported improved median and 2-year survival for patients with glioblastoma treated with concomitant and adjuvant temozolomide and radiotherapy. We report the final results with a median follow-up of more than 5 years.
Temozolomide (TMZ) is the standard of care for patients with newly diagnosed glioblastoma (GBM) as well as those with recurrent anaplastic glioma (AG) and GBM. It has become common practice to re-expose patients to TMZ who had been previously treated with TMZ, or to switch patients to alternative dosing regimens of TMZ when there are signs of relapse or progress on standard TMZ therapeutic regimens. To date, however, there is a scarcity of data on the efficacy of this therapeutic strategy, currently referred to as TMZ rechallenge. We have conducted a retrospective review of patients with recurrent glioma rechallenged with TMZ. Patients experiencing progressive disease (PD) during TMZ therapy who were rechallenged with alternative TMZ regimens and patients rechallenged after stable disease in a TMZ-free interval were evaluated separately. A total of 90 rechallenges were identified in 80 patients. The progression-free survival at 6 months (PFS-6) was 48% in patients with AG (12/25) and 27.7% in those with GBM (14/47). The PFS-6 was 16.7% in AG and 26.3% in GBM for patients switched during TMZ and 57.9 and 28.6% in patients rechallenged after a TMZ-free interval of at least 8 weeks. Relevant hematological toxicity (NCI-CTC grade 3-5) was observed in 22 of 90 rechallenges, and relevant non-hematological in ten of 90 rechallenges. Temozolomide was well tolerated and generated promising PFS-6 in patients who had previously failed TMZ, regardless if they progressed during TMZ treatment, or if they were rechallenged after a TMZ-free interval. These results suggest that the TMZ rechallenge strategy warrants further investigation in a prospective randomized trial.
Although the protooncogene c-Jun plays a critical role in cell proliferation, cell death, and malignant transformation, DNA microarray screens have identified only a few human cancer types with aberrant expression of c-Jun. Here, we show that c-Jun accumulation is robustly elevated in human glioblastoma and that this increase contributes to the malignant properties of the cells. Most importantly, the increase in c-Jun protein accumulation occurs with no corresponding increase in c-Jun mRNA or the half-life of the c-Jun protein but, rather, in the translatability of the transcript. The c-Jun 5UTR harbors a potent internal ribosomal entry site (IRES) with a virus-like IRES domain that directs cap-independent translation in glioblastoma cells. Accumulation of c-Jun is not dependent on MAPK activity but can be stimulated by a cytoskeleton-dependent pathway. Our findings provide evidence that human c-Jun is an IRES-containing cellular transcript that contributes to cancer development through translational activation. This previously undescribed mechanism of c-Jun regulation might also be relevant to other types of human cancer and offers unique potential targets for therapy.
Lactate formation in highly proliferative tumors such as malignant gliomas is associated with poor survival and contributes to the suppression of local immunity. Here, we report that diclofenac used at nontoxic concentrations significantly decreased lactate production in murine glioma cells and inhibited the expression of lactate dehydrogenase-A in vitro. Lactate reduction was accompanied by a dose-dependent inhibition of cell growth and a cell cycle arrest at the G2/M checkpoint. In the presence of diclofenac, murine bone marrow-derived dendritic cells (DCs) showed enhanced IL-12, but decreased IL-10 secretion on Toll-like receptor stimulation with R848 that correlated with reduced lactate levels in the glioma cell coculture and a blockade of signal transducers and activators of transcription 3 phosphorylation. In vivo, diclofenac treatment diminished intratumoral lactate levels and resulted in a significant delay of glioma growth. Ex vivo analyses revealed that tumor-infiltrating DCs regained their capacity to produce IL-12 on R848 stimulation. Moreover, diclofenac reduced the number of tumor-infiltrating regulatory T cells and impaired the upregulation of the Treg activation marker CD25. Nevertheless, a single intratumoral injection of R848 combined with diclofenac failed to induce an additional survival advantage in glioma-bearing mice. Further analyses illustrated that the presence of diclofenac during T-cell activation compromised INF-? production and T-cell proliferation, indicating that immunotherapeutic approaches have to be carefully timed when combined with diclofenac. In summary, diclofenac appears as an attractive agent for targeting lactate production and counteracting local immune suppression in malignant gliomas.
Immune cell infiltration varies widely between different glioblastomas (GBMs). The underlying mechanism, however, remains unknown. Here we show that TGF-beta regulates proliferation, migration, and tumorigenicity of mesenchymal GBM cancer stem cells (CSCs) in vivo and in vitro. In contrast, proneural GBM CSCs resisted TGF-beta due to TGFR2 deficiency. In vivo, a substantially increased infiltration of immune cells was observed in mesenchymal GBMs, while immune infiltrates were rare in proneural GBMs. On a functional level, proneural CSC lines caused a significantly stronger TGF-beta-dependent suppression of NKG2D expression on CD8(+) T and NK cells in vitro providing a mechanistic explanation for the reduced immune infiltration of proneural GBMs. Thus, the molecular subtype of CSCs TGF-beta-dependently contributes to the degree of immune infiltration.
The effectiveness of temozolomide (TMZ) dosing schemes and the "rechallenge" of recurrent glioblastoma (GBM) with TMZ are controversial. We therefore compared the efficacy of different TMZ dosing schemes against GBM cancer stem cell (CSC) lines in vitro. In O(6)-methyl-guanidine-methyl-transferase (MGMT)-negative CSC lines, all schedules (1 day on/27 days off, 5 days on/23 days off, 7 days on/7 days off, 21 days on/7 days off, continuous low-dose TMZ) depleted clonogenic cells. In TMZ-resistant CSC lines, the 7 days on/7 days off scheme showed higher toxicity as compared with the other schemes. However, clinically feasible concentrations remained ineffective in highly resistant CSC lines. In addition, none of the schedules induced long-term depletion of clonogenic cells even at the highest concentrations (up to 250 ?M). After sublethal TMZ treatment for 5 days, TMZ rechallenge of recovering CSC lines remained effective. Our data advocate CSC lines as in vitro model to address clinical questions. Using this model, our data suggest the effectiveness of TMZ in MGMT-negative CSC lines and support the concept of TMZ rechallenge. The 7 days on/7 days off scheme consistently showed the best activity of all schedules in TMZ-resistant CSC lines.
Introduction: Polyarteritis nodosa (PAN) is a necrotizing vasculitis of smallto-medium-sized vessels, rarely associated with hematologic neoplasms. Case report: We report a 44-year-old man with a history of monoclonal gammopathy of undetermined significance (MGUS) who presented with rapidly progressing sensorimotor peripheral neuropathy. Two weeks after onset the patient developed severe acute acral and retinal ischemia. MR-angiography and nerve biopsy revealed a systemic necrotizing vasculitis (PAN type). At this time, bone marrow biopsy identified a smoldering multiple myeloma. Immediate immunosuppressive and anti-neoplastic treatment (steroids, immunoglobulins, bortezomib combined with cyclophosphamide followed by lenalidomide maintenance) resulted in a favorable clinical outcome. After 4 years, the patient is in good clinical condition with sustained partial remission from myeloma and without evidence of relapse of PAN. Conclusion: This is a remarkable case of a histologically confirmed peripheral neuropathy due to polyarteritis nodosa associated with progression of MGUS to multiple myeloma. Immediate diagnosis and combined immunosuppressive and anti-neoplastic treatment may improve the outcome of this potentially life-threatening clinical condition.
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