Glioblastoma Multiforme Brain Tumors Research Articles

MicroRNAs and glioblastoma; the stem cell connection

Recent data draw close parallels between cancer, including glial brain tumors, and the biology of stem and progenitor cells. At the same time, it has become clear that one of the major roles that microRNAs play is in the regulation of stem cell biology, differentiation, and cell 'identity'. For example, microRNAs have been increasingly implicated in the regulation of neural differentiation. Interestingly, initial studies in the incurable brain tumor glioblastoma multiforme strongly suggest that microRNAs involved in neural development play a role in this disease. This encourages the idea that certain miRs allow continued tumor growth through the suppression of differentiation and the maintenance of the stem cell-like properties of tumor cells. These concepts will be explored in this article.

Controlling brain tumor growth by intraventricular administration of an AAV vector encoding IFN-β

Glioblastoma multiforme (GBM) is the most aggressive type of all primary brain tumors, with an overall median survival <1 year after diagnosis. Despite introduction of multimodal treatment approaches, the prognosis has not improved significantly over the past 50 years. In this study we investigated the effect of intracerebroventricular (ICV) injection of an adeno-associated virus (AAV) vector encoding human interferon-beta (AAV-hIFN-beta) on glioblastoma growth. Recently, we found that peritumoral parenchymal transduction with an AAV-hIFN-beta was exceptionally efficient in eradicating GBM brain tumors. However, the extensive infiltration and migration displayed by glioblastoma cells in patients may leave a significant number of tumor cells outside a local therapeutic zone created by intraparenchymal delivery of AAV vectors. Here we show that pretreatment of mice by ICV infusion of an AAV-IFN-beta completely prevents tumor growth in an orthotopic model of GBM. Furthermore, ICV infusion of AAV-IFN-beta into mice bearing preestablished U87 intracranial tumors improved their survival compared to mice infused through the same route with a control AAV vector. These data suggest that ICV injection of AAV vectors encoding antitumor proteins is a promising approach deserving further consideration for the treatment of GBM.

The induction of orphan nuclear receptor Nur77 expression by n- butylenephthalide aspharmaceuticals on hepatocellular carcinoma (HCC) cells therapy

N-Butylidenephthalide (BP), isolated from the chloroform extract of Angelica sinensis, has been examined for its antitumor effects on glioblastoma multiforme brain tumors; however, little is known about its antitumor effects on hepatocellular carcinoma cells. Two hepatocellular carcinoma cell lines, HepG2 and J5, were treated with either N-butylidenephthalide or a vehicle, and cell viability and apoptosis were evaluated. Apoptosis-related mRNA and proteins expressed, including orphan receptor family Nurr1, NOR-1, and Nur77, were evaluated as well as the effect of N-butylidenephthalide in an in vivo xenograft model. N-Butylidenephthalide caused growth inhibition of both the cell lines at 25 g/ml. Furthermore, N-butylidenephthalide-induced apoptosis seems to be related to Nur77 translocation from nucleus to cytosol, which leads to cytochrome c release and caspase-3-dependent apoptosis. N-Butylidenephthalide-related tumor apoptosis was associated with phosphatidylinositol 3-kinase/protein kinase B (AKT)/glycogen synthase kinase-3 rather than the mitogen-activated protein kinase or protein kinase C pathway. Blockade of AKT activation enhanced proliferation inhibition and the induction of phosphor-Bcl-2 and Nur77 proteins. Besides, the increasing apoptosis by BP via transfection wild-type cAMP-response element-binding protein (CREB) into tumor cell was suppressed by dominant phosphorylation site mutation of CREB. This finding suggested CREB pathway was also partly involved in tumor apoptosis caused by BP. Administration of N-butylidenephthalide showed similar antitumoral effects in both HepG2 and J5 xenograft tumors. N-Butylidenephthalide induced apoptosis in hepatocellular carcinoma cells, both in vitro and in vivo, suggesting a potential clinical use of this compound for improving the prognosis of hepatocellular carcinoma cells.

The Induction of Orphan Nuclear Receptor Nur77 Expression by n-Butylenephthalide as Pharmaceuticals on Hepatocellular Carcinoma Cell Therapy

N-butylidenephthalide (BP), isolated from the chloroform extract of Angelica sinensis, has been examined for its antitumor effects on glioblastoma multiforme brain tumors; however, little is known about its antitumor effects on hepatocellular carcinoma cells. Two hepatocellular carcinoma cell lines, HepG2 and J5, were treated with either N-butylidenephthalide or a vehicle, and cell viability and apoptosis were evaluated. Apoptosis-related mRNA and proteins expressed, including orphan receptor family Nurr1, NOR-1, and Nur77, were evaluated as well as the effect of N-butylidenephthalide in an in vivo xenograft model. N-butylidenephthalide caused growth inhibition of both the cell lines at 25 microg/ml. Furthermore, N-butylidenephthalide-induced apoptosis seems to be related to Nur77 translocation from nucleus to cytosol, which leads to cytochrome c release and caspase-3-dependent apoptosis. N-butylidenephthalide-related tumor apoptosis was associated with phosphatidylinositol 3-kinase/protein kinase B (AKT)/glycogen synthase kinase-3beta rather than the mitogen-activated protein kinase or protein kinase C pathway. Blockade of AKT activation enhanced proliferation inhibition and the induction of phosphor-Bcl-2 and Nur77 proteins. Besides, the increasing apoptosis by BP via transfection wild-type cAMP-response element-binding protein (CREB) into tumor cell was suppressed by dominant phosphorylation site mutation of CREB. This finding suggested CREB pathway was also partly involved in tumor apoptosis caused by BP. Administration of N-butylidenephthalide showed similar antitumoral effects in both HepG2 and J5 xenograft tumors. N-Butylidenephthalide induced apoptosis in hepatocellular carcinoma cells, both in vitro and in vivo, suggesting a potential clinical use of this compound for improving the prognosis of hepatocellular carcinoma cells.

Efficient Multilevel Brain Tumor Segmentation With Integrated Bayesian Model Classification

We present a new method for automatic segmentation of heterogeneous image data that takes a step toward bridging the gap between bottom-up affinity-based segmentation methods and top-down generative model based approaches. The main contribution of the paper is a Bayesian formulation for incorporating soft model assignments into the calculation of affinities, which are conventionally model free. We integrate the resulting model-aware affinities into the multilevel segmentation by weighted aggregation algorithm, and apply the technique to the task of detecting and segmenting brain tumor and edema in multichannel magnetic resonance (MR) volumes. The computationally efficient method runs orders of magnitude faster than current state-of-the-art techniques giving comparable or improved results. Our quantitative results indicate the benefit of incorporating model-aware affinities into the segmentation process for the difficult case of glioblastoma multiforme brain tumor.

Supervised pattern recognition for the prediction of contrast-enhancement appearance in brain tumors from multivariate magnetic resonance imaging and spectroscopy

The purpose of this study was to develop a pattern classification algorithm for use in predicting the location of new contrast-enhancement in brain tumor patients using data obtained via multivariate magnetic resonance (MR) imaging from a prior scan. We also explore the use of feature selection or weighting in improving the accuracy of the pattern classifier. Contrast-enhanced MR images, perfusion images, diffusion images, and proton spectroscopic imaging data were obtained from 26 patients with glioblastoma multiforme brain tumors, divided into a design set and an unseen test set for verification of results. A k-NN algorithm was implemented to classify unknown data based on a set of training data with ground truth derived from post-treatment contrast-enhanced images; the quality of the k-NN results was evaluated using a leave-one-out cross-validation method. A genetic algorithm was implemented to select optimal features and feature weights for the k-NN algorithm. The binary representation of the weights was varied from 1 to 4 bits. Each individual parameter was thresholded as a simple classification technique, and the results compared with the k-NN. The feature selection k-NN was able to achieve a sensitivity of 0.78+/-0.18 and specificity of 0.79+/-0.06 on the holdout test data using only 7 of the 38 original features. Similar results were obtained with non-binary weights, but using a larger number of features. Overfitting was also observed in the higher bit representations. The best single-variable classifier, based on a choline-to-NAA abnormality index computed from spectroscopic data, achieved a sensitivity of 0.79+/-0.20 and specificity of 0.71+/-0.11. The k-NN results had lower variation across patients than the single-variable classifiers. We have demonstrated that the optimized k-NN rule could be used for quantitative analysis of multivariate images, and be applied to a specific clinical research question. Selecting features was found to be useful in improving the accuracy of feature weighting algorithms and improving the comprehensibility of the results. We believe that in addition to lending insight into parameter relevance, such algorithms may be useful in aiding radiological interpretation of complex multimodality datasets.

Coactivation of Receptor Tyrosine Kinases Affects the Response of Tumor Cells to Targeted Therapies

Targeted therapies that inhibit receptor tyrosine kinases (RTKs) and the downstream phosphatidylinositol 3-kinase (PI3K) signaling pathway have shown promising anticancer activity, but their efficacy in the brain tumor glioblastoma multiforme (GBM) and other solid tumors has been modest. We hypothesized that multiple RTKs are coactivated in these tumors and that redundant inputs drive and maintain downstream signaling, thereby limiting the efficacy of therapies targeting single RTKs. Tumor cell lines, xenotransplants, and primary tumors indeed show multiple concomitantly activated RTKs. Combinations of RTK inhibitors and/or RNA interference, but not single agents, decreased signaling, cell survival, and anchorage-independent growth even in glioma cells deficient in PTEN, a frequently inactivated inhibitor of PI3K. Thus, effective GBM therapy may require combined regimens targeting multiple RTKs.

Phase I clinical pharmacokinetics of RTA 744: A blood brain barrier penetrating anthracycline active against high-grade glioma

2045 Background: Preclinical studies demonstrated that RTA 744, a 4’-O benzyl anthracycline designed to circumvent P-gp and MRP1-mediated efflux, effectively crosses the BBB, is retained in brain &amp; brain tumor tissue for &gt;24 hrs, and has demonstrated in vivo activity against glioblastoma multiforme (GBM) in an orthotopic model. Methods: We designed a multicenter, phase I dose- escalation study of RTA 744 administered as a short intravenous infusion for 3 consecutive days, every 3 weeks. Patients enrolled in the study were adult patients with recurrent or refractory GBM, anaplastic astrocytoma, or other primary brain tumors. Peripheral blood samples for PK analysis were collected prior to and at selected timepoints from 5 min to 96 hrs after drug administration, and quantified by LC/MS/MS. PK parameters describing RTA 744 disposition were determined by fitting compartmental models to individual patient plasma concentration-time data. Results: Twenty patients have been enrolled at daily doses ranging from 1.2 to 9.6 mg/m2. Mean (range) population terminal half-life was 34.6 (20.5–89.2) hrs, plasma drug clearance was 45.0 (27.4–86.9) L/hr/m2, and Vss was 1942 (684.9–4721.7) L/m2; population PK values reported for doxorubicin are 20–32 hrs, 24–35 L/hr/m2, and 700–1100 L/m2, respectively. Regimen related toxicity has been minimal with the most common adverse event being myelosuppression. Percentage of unchanged parent drug renally eliminated was 2.4% (0.42–6.03%). Several partial responses and one complete response have been noted, even at dose levels below the observed MTD of 7.5 mg/m2/day. Conclusions: These results are similar to what we have observed in our preclinical studies, demonstrating increased lipophillicity and enhanced biodistribution of RTA 744 when compared to doxorubicin. Direct confirmation of drug penetration into the CNS has not been determined in this study, however this is the focus of an ongoing trial in patients with leptomenigeal malignancies. No significant financial relationships to disclose.

Dynamics and Pattern Formation in Invasive Tumor Growth

We study the in vitro dynamics of the malignant brain tumor glioblastoma multiforme. The growing tumor consists of a dense proliferating zone and an outer less dense invasive region. Experiments with different types of cells show qualitatively different behavior: one cell line invades in a spherically symmetric manner, but another gives rise to branches. We formulate a model for this sort of growth using two coupled reaction-diffusion equations for the cell and nutrient concentrations. When the ratio of the nutrient and cell diffusion coefficients exceeds some critical value, the plane propagating front becomes unstable with respect to transversal perturbations. The instability threshold and the full phase-plane diagram in the parameter space are determined. The results are in a qualitative agreement with experimental findings for the two types of cells.

Alzheimer pathology in elderly patients with glioblastoma multiforme.

Alzheimer disease (AD) and glioblastoma multiforme (GBM) have similar peak, age-specific incidence rates; however, to my knowledge, only 1 case of GBM associated with AD has been reported to date. The frequency of AD pathology, including neuritic plaques, diffuse plaques, neurofibrillary tangles, and cerebral amyloid angiopathy in patients with GBM is unknown. Studies of cancer occurrence in patients with AD are contradictory, with frequencies reported as equal to and as less than that in the general population. The GBM/AD nonconcordance may reflect underreporting of AD pathology or other factors. To compare the frequency and extent of neocortical AD pathology in autopsy cases involving patients aged 60 to 82 years, both with and without GBM. Design.-Case-control study. Setting.-Pathology department of a university hospital. Thirty-six autopsy cases of GBM patients aged 60 to 82 years; 54 cases of patients in the same age group without GBM or other primary brain tumors. Examination of tumor sections for GBM and of neocortical sections for AD pathology according to Consortium to Establish a Registry for Alzheimer Disease (CERAD) guidelines. Glioblastoma multiforme was confirmed in all tumor cases. Alzheimer disease pathology was present in 42% of cases with GBM and in 48% of cases without GBM; 28% of GBM cases had CERAD age-related plaque scores indicative or suggestive of AD; 43% of cases without GBM had CERAD age-related plaque scores indicative or suggestive of AD. Alzheimer disease pathology was underreported in both GBM and non-GBM patients. The influence of neurodegenerative processes on GBM symptoms and therapy in elderly patients requires further study.

P53 function influences the effect of fractionated radiotherapy on glioblastoma tumors

Purpose: Glioblastoma multiforme brain tumors (GM) are treated with a spectrum of fractionation regimens based on the clinical and anatomical characteristics of the tumor but rarely based on the molecular characteristics of the individual neoplasm. This study tests the hypothesis that the response of cell lines derived from GM to fractionated radiotherapy depends on the function of wild-type p53 (wt p53), a tumor suppressor gene frequently mutated in GM tumors. Methods & Materials: Isogenic derivatives of glioblastoma cells differing only in p53 function were prepared using a retroviral vector expressing a dominant negative mutant of p53 (mt p53). Radiation survival in vitro was quantitated using linear quadratic and repair-saturation mathematical models. Apoptosis was assayed by a terminal deoxynucleotide transferase-labeling technique and chromatin morphology. Results: We have previously reported the generation of isogenic GM cell lines differing only in p53 function. U87-175.4, lacking wt p53 function, had a significantly lower α/β value than U87-LUX.8, expressing functional wt p53, leading us to hypothesize that fractionated irradiation would preferentially spare GM cells harboring mt p53 compared with those expressing functional, wt p53. Survival curves following either 2.0 Gy or 3.5 Gy/fraction demonstrated that lack of functional wt p53 was associated with resistance to fractionated irradiation. Radiation-induced apoptosis could not account for the observed differences in clonogenic survival. Rather, our data suggested that a deficit in the G1-checkpoint contributed to increased resistance to fractionated irradiation of cells expressing mutant p53. Conclusions: The effect of fractionated radiotherapy in GM may depend on the function of the tumor suppressor gene p53. A potential clinical consequence of these findings is that hyperfractionation regimens may provide a therapeutic advantage specifically for tumors expressing wt p53 whereas a radiotherapy course of fewer, larger fractions may be appropriate for the treatment of tumors carrying p53 mutations. Further studies are needed to confirm our proposal that the p53 status of GM tumors can be used to guide our choice of fractionation schemes.