Oncology Intelligence

Tuesday, September 20, 2016 11:21 AM|Malcolm F.G Stevens|RSC - Med. Chem. Commun. latest articles|Labels: brain cancer, glioma
Med. Chem. Commun., 2016, Accepted Manuscript
DOI: 10.1039/C6MD00384B, Research Article
David Cousin, Jihong Zhang, Marc Hummersone, Charles Matthews, Mark Frigerio, Tracey D Bradshaw, Malcolm F.G Stevens
Synthetic routes to 3-substituted imidazo[5,1-d]-1,2,3,5-tetrazines structurally related to temozolomide were explored. Interaction of 4-diazoimidazole-5-carboxamide with an isocyanate afforded high product yields when the isocyanate was available in acceptable purity. Alternatively,...
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Sunday, September 18, 2016 10:27 AM|Head and Neck Oncology|Labels: PI3K, brain cancer, clinical trial, glioma
ARID1A plays an important role in malignant tumorigenesis, but its role in gliomas remains unclear. This study aims to identify a possible biomarker that could be used in the diagnosis and tumor grade assessment of gliomas. Additionally, the biological role of ARID1A was further characterized in glioma cells. Data was collected from sporadic gliomas specimens (n = 55) and normal brain tissues (n = 5), and ARID1A expression was examined by quantitative RT PCR and western blot. We verified the differential expression of ARID1A and evaluated the associations of ARID1A expression with the pathologic characteristics of gliomas. An ARID1A overexpression plasmid was constructed and transfected into the human glioblastoma cell line U87, and cell proliferation and apoptosis were examined. Our results showed that the ARID1A mRNA in gliomas was significantly down regulated compared to that in normal brain tissues. As the pathological grade (World Health Organization (WHO) classification 2007) increased, the expression of ARID1A is decreased. Overexpression of ARID1A was able to inhibit cell proliferation and arrest cell cycle progression in the G1/S phase, as well as induce cell apoptosis in glioma cells. Furthermore, ARID1A overexpression was accompanied by suppression of glioma cell proliferation via the PI3K pathway and decreased expression of pAKT and pS6K. Therefore, ARID1A may be a useful target for the diagnosis and therapy of gliomas.
Friday, September 16, 2016 4:27 PM|Liang Xia, Caixing Sun, Qinglin Li, Fang Feng, Enqi Qiao, Limin Jiang, Bin Wu, Minghua Ge|International Journal of Biological Sciences|Labels: CDK, brain cancer, glioma

BACKGROUND: As a member of the CELF family, CELF1 (CUG-binding protein 1, CUGBP1) is involved in cardiac and embryonic development, skeletal muscle differentiation and mammary epithelial cell proliferation. CELF1 is also observed in many kinds of cancer and may play a great role in tumorigenesis and deterioration. However, the expression and mechanism of its function in human glioma remain unclear.

METHODS: We examined CELF1 expression in 62 glioma patients by immunohistochemistry and Western blot. The association between the expression of CELF1 protein and clinicopathological characteristics was analysed using SPSS 17.0. Survival analyses were performed using the Kaplan-Meier method. Small-interfering RNA was utilised to specifically knockdown CELF1 mRNA in U87 and U251 cells. Cell proliferation, cell cycle and cell apoptosis were tested by Cell Counting Kit-8 and flow cytometry. The expression of cell cycle-related gene CDKN1B was investigated by Western blot. The interactions between CELF1 and CDKN1B were detected with immune co-precipitation. Subcutaneous tumour models were used to study the effect of CELF1 on the growth of glioma cells in vivo.

RESULTS: Our results showed that CELF1 protein was frequently up-regulated in human glioma tissues. The expression level of this protein was positively correlated with glioma World Health Organisation grade and inversely correlated with patient survival (P < 0.05). Knockdown of CELF1 inhibited the glioma cell cycle process and proliferation potential, possibly by down-regulating its target, CDKN1B protein.

CONCLUSIONS: Results indicated that CELF1 may be a novel independent prognostic predictor of survival for glioma patients. It may promote glioma cell proliferation and cell cycle process during glioma carcinogenesis.

Friday, September 16, 2016 4:27 PM|Taemoon Chung, Juri Na, Young-il Kim, Da-Young Chang, Young Il Kim, Hyeonjin Kim, Ho Eun Moon, Keon Wook Kang, Dong Soo Lee, June-Key Chung, Sung-Soo Kim, Haeyoung Suh-Kim, Sun Ha Paek, Hyewon Youn|Theranostics|Labels: brain cancer, glioma

We investigated a therapeutic strategy for recurrent malignant gliomas using mesenchymal stem cells (MSC), expressing cytosine deaminase (CD), and prodrug 5-Fluorocytosine (5-FC) as a more specific and less toxic option. MSCs are emerging as a novel cell therapeutic agent with a cancer-targeting property, and CD is considered a promising enzyme in cancer gene therapy which can convert non-toxic 5-FC to toxic 5-Fluorouracil (5-FU). Therefore, use of prodrug 5-FC can minimize normal cell toxicity. Analyses of microarrays revealed that targeting DNA damage and its repair is a selectable option for gliomas after the standard chemo/radio-therapy. 5-FU is the most frequently used anti-cancer drug, which induces DNA breaks. Because dihydropyrimidine dehydrogenase (DPD) was reported to be involved in 5-FU metabolism to block DNA damage, we compared the survival rate with 5-FU treatment and the level of DPD expression in 15 different glioma cell lines. DPD-deficient cells showed higher sensitivity to 5-FU, and the regulation of DPD level by either siRNA or overexpression was directly related to the 5-FU sensitivity. For MSC/CD with 5-FC therapy, DPD-deficient cells such as U87MG, GBM28, and GBM37 showed higher sensitivity compared to DPD-high U373 cells. Effective inhibition of tumor growth was also observed in an orthotopic mouse model using DPD- deficient U87MG, indicating that DPD gene expression is indeed closely related to the efficacy of MSC/CD-mediated 5-FC therapy. Our results suggested that DPD can be used as a biomarker for selecting glioma patients who may possibly benefit from this therapy.

Friday, September 16, 2016 4:27 PM|Alessia Lo Dico, Viviana Costa, Cristina Martelli, Cecilia Diceglie, Francesca Rajata, Aroldo Rizzo, Carmine Mancone, Marco Tripodi, Luisa Ottobrini, Riccardo Alessandro, Alice Conigliaro|Theranostics|Labels: HIF, brain cancer, glioma

Hypoxia is a common feature in solid tumours. In glioma, it is considered the major driving force for tumour angiogenesis and correlates with enhanced resistance to conventional therapies, increased invasiveness and a poor prognosis for patients. Here we describe, for the first time, that miR675-5p, embedded in hypoxia-induced long non-coding RNA H19, plays a mandatory role in establishing a hypoxic response and in promoting hypoxia-mediated angiogenesis. We demonstrated, in vitro and in vivo, that miR675-5p over expression in normoxia is sufficient to induce a hypoxic moreover, miR675-5p depletion in low oxygen conditions, drastically abolishes hypoxic responses including angiogenesis. In addition, our data indicate an interaction of miR675-5p, HIF-1α mRNA and the RNA Binding Protein HuR in hypoxia-induced responses. We suggest the modulation of miR675-5p as a new therapeutic option to promote or abolish hypoxia induced angiogenesis.

Friday, September 16, 2016 11:13 AM|Ramachandran, M., Yu, D., Dyczynski, M., Baskaran, S., Zhang, L., Saul, S., Lulla, A., Lulla, V., Nelander, S., Dimberg, A., Merits, A., Leja-Jarblad, J., Essand, M.|Clinical Cancer Research Online First Articles|Labels: brain cancer, glioma

Purpose:: Glioblastoma multiforme (GBM) and high–risk neuroblastoma are cancers with poor outcome. Immunotherapy in the form of neurotropic oncolytic viruses is a promising therapeutic strategy for these malignancies. Here we evaluate the oncolytic potential of the neurovirulent and partly interferon (IFN)–β–resistant Semliki Forest virus (SFV)–4 in GBMs and neuroblastomas. To reduce neurovirulence we constructed SFV4miRT, which is attenuated in normal CNS cells through insertion of microRNA target sequences for miR124, miR125, miR134 Experimental Design:Oncolytic activity of SFV4miRT was examined in mouse neuroblastoma and GBM cell lines and in patient–derived human glioblastoma cell cultures (HGCC). In vivo neurovirulence and therapeutic efficacy was evaluated in two syngeneic orthotopic glioma models (CT–2A, GL261) and syngeneic subcutaneous neuroblastoma model (NXS2). The role of IFN–β in inhibiting therapeutic efficacy was investigated. Results:The introduction of microRNA target sequences reduced neurovirulence of SFV4 in terms of attenuated replication in mouse CNS cells and ability to cause encephalitis when administered intravenously. A single intravenous injection of SFV4miRT prolonged survival and cured 4 of 8 mice (50%) with NXS2 and 3 of 11 mice (27%) with CT–2A, but not for GL261 tumor bearing mice. In vivo therapeutic efficacy in different tumor models inversely correlated to secretion of IFN–β by respective cells upon SFV4 infection in vitro. Similarly, killing efficacy of HGCC lines inversely correlated to IFN–β response and interferon–α/β receptor (IFNAR)–1 expression. Conclusions:SFV4miRT has reduced neurovirulence, while retaining its oncolytic potential. SFV4miRT is an excellent candidate for treatment of GBMs and neuroblastomas with low IFN–β secretion.

Friday, September 16, 2016 7:08 AM|Rampling, R., Peoples, S., Mulholland, P. J., James, A., Al-Salihi, O., Twelves, C. J., McBain, C., Jefferies, S., Jackson, A., Stewart, W., Lindner, J., Kutscher, S., Hilf, N., McGuigan, L., Peters, J., Hill, K., Schoor, O., Singh-Jasuja, H., Halford, S. E., Ritchie, J. W. A.|Clinical Cancer Research Online First Articles|Labels: brain cancer, clinical trial, glioma

Purpose: To perform a two-cohort, phase I safety and immunogenicity study of IMA950 in addition to standard chemoradiotherapy and adjuvant temozolomide in patients with newly diagnosed glioblastoma. IMA950 is a novel glioblastoma-specific therapeutic vaccine containing 11 tumor-associated peptides (TUMAP), identified on human leukocyte antigen (HLA) surface receptors in primary human glioblastoma tissue.

Experimental Design: Patients were HLA-A*02–positive and had undergone tumor resection. Vaccination comprised 11 intradermal injections with IMA950 plus granulocyte macrophage colony-stimulating factor (GM-CSF) over a 24-week period, beginning 7 to 14 days prior to initiation of chemoradiotherapy (Cohort 1) or 7 days after chemoradiotherapy (Cohort 2). Safety was assessed according to NCI CTCAE Version 4.0 and TUMAP-specific T-cell immune responses determined. Secondary observations included progression-free survival (PFS), pretreatment regulatory T cell (Treg) levels, and the effect of steroids on T-cell responses.

Results: Forty-five patients were recruited. Related adverse events included minor injection site reactions, rash, pruritus, fatigue, neutropenia and single cases of allergic reaction, anemia and anaphylaxis. Two patients experienced grade 3 dose-limiting toxicity of fatigue and anaphylaxis. Of 40 evaluable patients, 36 were TUMAP responders and 20 were multi-TUMAP responders, with no important differences between cohorts. No effect of pretreatment Treg levels on IMA950 immunogenicity was observed, and steroids did not affect TUMAP responses. PFS rates were 74% at 6 months and 31% at 9 months.

Conclusions: IMA950 plus GM-CSF was well-tolerated with the primary immunogenicity endpoint of observing multi-TUMAP responses in at least 30% of patients exceeded. Further development of IMA950 is encouraged. Clin Cancer Res; 22(19); 1–10. ©2016 AACR.

See related commentary by Lowenstein and Castro, p. 4760

Friday, September 16, 2016 7:08 AM|Lowenstein, P. R., Castro, M. G.|Clinical Cancer Research Online First Articles|Labels: brain cancer, clinical trial, glioma

A novel approach to immunization against glioma tumors is described. Immunization against 11 antigens expressed in malignant brain tumors elicits responses to one or more antigens in a large percentage of patients. This novel approach suggests that it could be extended to a phase III trial. Clin Cancer Res; 22(19); 1–3. ©2016 AACR.

See related article by Rampling et al., p. 4776

Thursday, September 15, 2016 7:51 PM|Haidar A. Shamran, Haidar F. Ghazi, Ahmed AL-Salman, Ahmad A. Al-Juboory, Dennis D. Taub, Robert L. Price, Mitzi Nagarkatti, Prakash S. Nagarkatti, Udai P. Singh|International Journal of Medical Sciences|Labels: brain cancer, IL, glioma

Glioma is one of the most aggressive and most common tumors of the central nervous system (CNS) in humans. The exact causes of glioma are not well known, but evidence suggests the involvement of genetic factors in addition to environmental risk factors. The present study aimed to determine whether polymorphisms in IL-10-1082A/G, IL-12p40 1188C/A, and IL-13+2044G/A (rs20541) are associated with the incidence of glioma in Iraqi patients. Ninety-six patients with different grades of glioma and 40 apparently healthy individuals were recruited. A blood sample and genomic DNA were collected from all subjects. The amplification refractory mutation system and sequence-specific primer polymerase chain reaction (PCR) were used for genotyping of IL-10-1082A/G and IL-12p40 1188C/A, respectively; whereas, the IL-13+2044G/A was detected by DNA sequencing after amplification of the genes by PCR.

All SNPs were within Hardy-Weinberg equilibrium and each appeared in three genotypes in patients and controls. In IL-10-1082A/G, these genotypes frequencies were AA (75%), AG (22.93%) and GG (2.07%) in patients as compared to similar frequencies (62.5%), (27.5%) and (10%) respectively, in controls. The variant IL-12p40 1188C/A genotype was AA (72.92%), AC (23.96%), and CC (3.13%%) in patients as compared to 65%, 30%, and 5%, respectively, in controls. The frequencies of IL-13+2044G/A genotypes (GG, GA, and AA) were 89.58%, 9.37%, and 1.04% among patients versus 47.5%, 32.5% and 20%, respectively, among controls. These results suggest a protective role of mutant alleles G and A in IL-10-1082A/G and IL-13+2044G/A against gliomas. Further studies with more rigorous parameter designs will be needed to confirm the current findings.

Thursday, September 15, 2016 9:10 AM|Pointer, K. B., Clark, P. A., Eliceiri, K. W., Salamat, M. S., Robertson, G. A., Kuo, J. S.|Clinical Cancer Research Online First Articles|Labels: brain cancer, glioma

Purpose:Glioblastoma(GBM) is the most malignant primary brain tumor, with a median survival of less than two years. More effective therapeutic approaches are needed to improve clinical outcomes. Experimental Design:Glioblastoma patient-derived cells(GPDCs) were isolated from patient GBMs and implanted in mice to form xenografts. Immunohistochemistry was performed for hERG expression and tumor proliferation. Sphere-forming assays with hERG blocker E-4031 were performed on a highand low hERG expressing lines. A GBM TMA(115 patients) was used to correlate hERG expression with patient survival. Clinical data was analyzed to determine if patient survival was affected by incidental administration of hERG inhibitory drugs, and the correlative effect of patient GBM hERG expression levels. Results:hERG expression was upregulated in GBM xenografts with higher proliferative indices. High hERG-expressing GPDCs showed a reduction in sphere formation when treated with hERG inhibitors compared to low hERG-expressing GPDCs. GBM TMA analysis showed worse survival for GBM patients with high hERG expression versus low expression, 43.5 vs. 60.9 weeks respectively (p= 0.022). Furthermore, patients who received at least one hERG blocker had a better survival rate compared to patients who did not (p=0.0015). Subgroup analysis showed that GBM patients with high hERG expression who received hERG blockers had improved survival (p=0.0458). There was no difference in survival for low hERG-expressing GBM patients who received hERG blockers (p=0.4136). Conclusions:Our findings suggest that hERG is a potential GBM survival marker, and that already approved drugs with non-torsadogenic hERG inhibitory activity may potentially be re-purposed as adjuvant GBM therapy in high hERG-expressing GBM patients.

Thursday, September 15, 2016 6:45 AM|Dominguez-Valentin, M., Gras Navarro, A., Rahman, A. M., Kumar, S., Retiere, C., Ulvestad, E., Kristensen, V., Lund–Johansen, M., Lie, B. A., Enger, P. O., Nȷolstad, G., Kristoffersen, E., Lie, S. A., Chekenya, M.|Cancer Research recent issues|Labels: brain cancer, glioma
By affecting immunological presentation, the presence of cytomegalovirus in some glioblastomas may impact progression. In this study, we examined a hypothesized role for natural killer (NK) cells in impacting disease progression in this setting. We characterized 108 glioblastoma patients and 454 healthy controls for HLA-A,-B,-C, NK-cell KIR receptors, and CMV-specific antibodies and correlated these metrics with clinical parameters. Exome sequences from a large validation set of glioblastoma patients and control individuals were examined from in silico databases. We demonstrated that the KIR allele KIR2DS4*00101 was independently prognostic of prolonged survival. KIR2DS4*00101 displayed 100% concordance with cognate HLA-C1 ligands in glioblastoma patients, but not controls. In the context of both HLA-C1/C2 ligands for the KIR2DS4 receptor, patient survival was further extended. Notably, all patients carrying KIR2DS4*00101 alleles were CMV seropositive, but not control individuals, and exhibited increased NK-cell subpopulations, which expressed the cytotoxicity receptors CD16, NKG2D, and CD94/NKG2C. Finally, healthy controls exhibited a reduced risk for developing glioblastoma if they carried two KIR2DS4*00101 alleles, where protection was greatest among Caucasian individuals. Our findings suggest that KIR2DS4*00101 may offer a molecular biomarker to identify intrinsically milder forms of glioblastoma. Cancer Res; 76(18); 5326–36. ©2016 AACR.
Wednesday, September 14, 2016 4:21 PM|Fred Hutchinson Cancer Research Center/UW Medicine Cancer Consortium - Clinical Trials|Labels: brain cancer, clinical trial, glioma
Radiation therapy uses high-energy x-rays to kill tumor cells. Drugs used in chemotherapy, such as temozolomide, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. It is not yet known whether giving temozolomide alone, radiation followed by PCV, or temozolomide together with radiation therapy followed by temozolomide is more effective in treating anaplastic glioma.
Wednesday, September 14, 2016 4:21 PM|Fred Hutchinson Cancer Research Center/UW Medicine Cancer Consortium - Clinical Trials|Labels: mTOR, brain cancer, clinical trial, glioma
This is an open label study of everolimus in children with recurrent or progressive low-grade glioma.
Tuesday, September 13, 2016 8:19 PM|Theo F. J. Kraus, Andrea Greiner, Martina Steinmaurer, Vanessa Dietinger, Virginie Guibourt, Hans A. Kretzschmar|Journal of Cancer (RSS 2.0)|Labels: brain cancer, glioma

The molecular mechanisms leading to brain tumors still remain unclear. Nevertheless, there is increasing evidence that epigenetic effects play crucial roles in tumor development and progression. Thereby, 5-hydroxymethylcytosine (5hmC) represents a further base modification of cytosine besides 5-methylcytosine (5mC). In addition to the role of 5hmC as an intermediate in demethylation, 5hmC is of reasonable importance for cellular control. Previous studies showed that loss of 5hmC is a hallmark of human malignancies, e.g. in glioma, melanoma, and myeloid tumors. In myeloid malignancies studies showed that loss of 5hmC was due to mutations within ten-eleven-translocation (TET) genes, enzymes being responsible for conversion of 5mC to 5hmC. Nevertheless, till date there are no genetic characterization data of TET enzymes available for glioma.

In this study, we genetically characterized TET2 and TET3 alterations in 50 human gliomas (WHO-Grade II-IV) and in 19 healthy brain samples. We identified 7 genetic alterations within TET2 (p.V218M, p.G355N, p.P363L, p.L1721W, p.P1723S, p.I1762V, p.H1778R). Additionally, we performed quantification of 5hmC amount and added functional prediction analysis of identified TET alterations to evaluate the biological impact of these alterations on the hydroxymethylome. An analysis of TET3 showed no non-synonymous alterations.

In summary, we did not find correlations of TET alterations with 5hmC amount. Thus, our data emphasize that, in contrast to leukemia, loss of 5hmC in glioma is not caused by TET gene alterations. Moreover, other disturbances, such as disrupted gene expressions or functional inhibitions of TET proteins may be responsible for the aberrant epigenome of human glioma.

Tuesday, September 13, 2016 8:19 PM|Derek Lee, Stella Sun, Xiao Qin Zhang, Ping De Zhang, Amy S.W. Ho, Karrie M.Y. Kiang, Ching Fai Fung, Wai Man Lui, Gilberto K.K. Leung|Journal of Cancer (RSS 2.0)|Labels: brain cancer, glioma

Glioblastoma multiforme (GBM) is the commonest primary brain tumour in adults characterized by relentless recurrence due to resistance towards the standard chemotherapeutic agent temozolomide (TMZ). Prolyl 4-hydroxylase, beta polypeptide (P4HB), an endoplasmic reticulum (ER) chaperone, is known to be upregulated in TMZ-resistant GBM cells. MicroRNAs (miRNAs) are non-protein-coding transcripts that may play important roles in GBM chemoresistance. We surmised that miRNA dysregulations may contribute to P4HB upregulation, hence chemoresistance. We found that miRNA-210 (miR-210) was P4HB-targeting and was highly downregulated in TMZ-resistant GBM cells. Forced overexpression of miR-210 led to P4HB downregulation and a reduction in TMZ-resistance. A reciprocal relationship between their expressions was also verified in clinical glioma specimens. Our study is the first to demonstrate a potential link between miR-210 and ER chaperone in determining chemosensitivity in GBM. The findings have important translational implications in suggesting new directions of future studies.

Tuesday, September 13, 2016 8:19 PM|Carolien A.E. Koks, Steven De Vleeschouwer, Norbert Graf, Stefaan W. Van Gool|Journal of Cancer (RSS 2.0)|Labels: brain cancer, clinical trial, glioma

Oncolytic viruses have been seriously considered for glioma therapy over the last 20 years. The oncolytic activity of several oncolytic strains has been demonstrated against human glioma cell lines and in in vivo xenotransplant models. So far, four of these stains have additionally completed the first phase I/II trials in relapsed glioma patients. Though safety and feasibility have been demonstrated, therapeutic efficacy in these initial trials, when described, was only minor. The role of the immune system in oncolytic virotherapy for glioma remained much less studied until recent years. When investigated, the immune system, adept at controlling viral infections, is often hypothesized to be a strong hurdle to successful oncolytic virotherapy. Several preclinical studies have therefore aimed to improve oncolytic virotherapy efficacy by combining it with immune suppression or evasion strategies. More recently however, a new paradigm has developed in the oncolytic virotherapy field stating that oncolytic virus-mediated tumor cell death can be accompanied by elicitation of potent activation of innate and adaptive anti-tumor immunity that greatly improves the efficacy of certain oncolytic strains. Therefore, it seems the three-way interaction between oncolytic virus, tumor and immune system is critical to the outcome of antitumor therapy. In this review we discuss the studies which have investigated how the immune system and oncolytic viruses interact in models of glioma. The novel insights generated here hold important implications for future research and should be incorporated into the design of novel clinical trials.

Tuesday, September 13, 2016 8:19 PM|Theo F. J. Kraus, Andrea Greiner, Virginie Guibourt, Kristina Lisec, Hans A. Kretzschmar|Journal of Cancer (RSS 2.0)|Labels: brain cancer, glioma

Background: Recent research indicates that long non-coding RNAs (lncRNA) represent a new family of RNAs that is of fundamental importance for controlling transcription and translation. Thereby, there is increasing evidence that lncRNAs are also important in tumourigenesis. Thereby valid expression profiling using quantitative PCR requires suitable, stably expressed normalisers to achieve reliable and reproducible data. However, no systematic analysis of suitable references in lncRNA studies in human glioma has been performed yet.

Methods: In this study, we investigated 90 lncRNAs in 30 tissue specimen for the expression stability in human diffuse astrocytoma (WHO-Grade II), anaplastic astrocytoma (WHO-Grade III) and glioblastoma (WHO-Grade IV) both alone as well as in comparison with normal white matter. Our identification procedure included a rigorous bioinformatical selection process that resulted in the inclusion of only highly abundant, equally expressed lncRNAs for further analysis. Additionally, lncRNAs were classified according to their stability value using the NormFinder algorithm.

Results: We identified 24 appropriate normalisers suitable for studies in diffuse astrocytoma, 22 for studies in anaplastic astrocytoma and 12 for studies in glioblastoma. Comparing all three glioma entities 7 lncRNAs showed stable expression levels. Addition of normal brain tissue resulted in only 4 suitable lncRNAs.

Conclusions: Our findings indicate that 4 lncRNAs (HOXA6as, H19 upstream conserved 1 and 2, Zfhx2as and BC200) are suitable as normalisers in glioma and normal brain. These lncRNAs may thus be regarded as universal references being applicable for the accurate normalisation of lncRNA expression profiling in various glioma (WHO-Grades II-IV) alone and in combination with brain tissue. This enables to perform valid longitudinal studies, e.g. of glioma before and after malignisation to identify changes of lncRNA expressions probably driving malignant transformation.

Tuesday, September 13, 2016 8:19 PM|Qianqian Wu, Yingwei Chang, Luping Zhang, Yuqiang Zhang, Ting Tian, Guoying Feng, Shuai Zhou, Qinyin Zheng, Fengchan Han, Fei Huang|Journal of Cancer|Labels: brain cancer, glioma

Glioma is among the ten most common causes of cancer-related death and has no effective treatment for it, so we are trying to find a new target for anticancer treatment. This study investigates the different expression of SRPK1 as a novel protein in glioma, which can influence tumor cells biological characteristics in normoxic and hypoxic environment. The expression levels of SRPK1 protein in glioma cell lines transfected with siSRPK1 or not were examined using immunofluorescence, RT-PCR and Western blot analysis, respectively. The impact of SRPK1 on the biological characteristics of U251 cells was further studied using methylthiazol tetrazolium assays, flow cytometry, and Transwell invasion chamber assays. The results showed that knockdown of SRPK1 inhibited tumor cells growth, invasion and migration in normoxic condition, but portion of the effect could be reversed in hypoxia. SRPK1 expression was induced in glioma cells by DDP treated, but not TMZ, in both normoxia and hypoxia conditions. We propose SRPK1 as a new molecular player contributing to the early treatment of glioma.

Tuesday, September 13, 2016 2:05 PM|Daina Skiriutė, Giedrius Steponaitis, Paulina Vaitkienė, Mykolas Mikučiūnas, Kęstutis Skauminas, Arimantas Tamašauskas, Arunas Kazlauskas|Journal of Cancer|Labels: brain cancer, glioma

Aims: NDRG2 (N-myc downstream regulated gene 2) gene is involved in important biological processes: cell differentiation, growth and apoptosis. Several molecular studies have shown NDRG2 as a promising diagnostic marker involved in brain tumor pathology. The aim of the study was to investigate how changes in epigenetic modification and activity of NDRG2 reflect on glioma malignancy and patient outcome. Methods: 137 different malignancy grade gliomas were used as the study material: 14 pilocytic astrocytomas grade I, 45 diffuse astrocytomas grade II, 29 anaplastic astrocytomas grade III, and 49 grade IV astrocytomas (glioblastomas). Promoter methylation analysis has been carried out by using methylation-specific PCR, whereas RT-PCR and Western-blot analyses were used to measure NDRG2 expression levels. Results: We demonstrated that NDRG2 gene methylation frequency increased whereas expression at both mRNA and protein levels markedly decreased in glioblastoma specimens compared to the lower grade astrocytomas. NDRG2 transcript and protein levels did not correlate with the promoter methylation state, suggesting the presence of alternative regulatory gene expression mechanisms that may operate in a tissue-specific manner in gliomas. Kaplan-Meier analyses revealed significant differences in survival time in gliomas stratified by NDRG2 methylation status and mRNA and protein expression levels. Conclusions: Our findings highlight the usefulness of combining epigenetic data to gene expression patterns at mRNA and protein level in tumor biomarker studies, and suggest that NDRG2 downregulation might bear influence on glioma tumor progression while being associated with higher malignancy grade.

Monday, September 12, 2016 1:00 AM|MIT Biotech Group - Essential Biotech RSS Feed|Labels: brain cancer, clinical trial, glioma
Novocure Ltd. (NASDAQ:NVCR) gained $0.53 to $8.62 on Monday after it said a long-term analysis of a Phase III study showed Optune (NovoTTF-100A) significantly improved survival after four years in patients with newly diagnosed glioblastoma multiforme.The 695-patient EF-14 study evaluated Optune alone or in combination with temozolomide. The company said it will present the analysis at next month's Society for Neuro-Oncology meeting in Scottsdale, Arizona. In an interim analysis of EF-14 published last year in JAMA, Optune significantly improved progression-free survival (HR=0.62; p=0.001) and overall survival (HR=0.64; p=0.004) compared to temozolomide alone. The interim analysis evaluated 315 patients with a median follow-up of 38 months. Optune is a non-invasive portable device that disrupts the division of cancer cells in the brain using alternating electric fields delivered by electrodes. FDA has approved Optune to treat newly diagnosed and recurrent glioblastoma.
Sunday, September 11, 2016 11:00 PM|Coelho, Paulo L.C.; Oliveira, Mona N.; da Silva, Alessandra B.; Pitanga, Bruno P.S.; Silva, Victor D.A.; Faria, Giselle P.; Sampaio, Geraldo P.; Costa, Maria de Fatima D.; Braga-de-Souza, Suzana; Costa, Silvia L.|Anti-Cancer Drugs - Published Ahead-of-Print|Labels: brain cancer, clinical trial, glioma
This study aimed to investigate the antitumor and immunomodulatory properties of the flavonoid apigenin (5,7,4'-trihydroxyflavone), which was extracted from Croton betulaster Mull, in glioma cell culture using the high-proliferative rat C6 glioma cell line as a model. Apigenin was found to have the ability to reduce the viability and proliferation of C6 cells in a time-dependent and dose-dependent manner, with an IC50 of 22.8 [micro]mol/l, 40 times lower than that of temozolomide (1000 [micro]mol/l), after 72 h of apigenin treatment. Even after C6 cells were treated with apigenin for 48 h, high proportions of C6 cells entered apoptosis (39.56%) and autophagy (22%) as shown by flow cytometry using annexin V/propidium iodide and acridine orange staining, respectively. In addition, the flavonoid apigenin induced cell accumulation in the G0/G1 phase of the cell cycle and inhibited glioma cell migration efficiently. Moreover, apigenin induced astroglial differentiation and morphological changes in C6 cells, characterized by increased expression of glial fibrillary acidic protein and decreased expression of nestin protein, a typical marker of neuronal precursors. The immunomodulating effects of apigenin were also characterized by a change in the inflammatory profile as evidenced by a significant decrease in interleukin-10 and tumor necrosis factor production and increased nitric oxide levels. Because apigenin can induce differentiation, apoptosis, and autophagy, can alter the profile of cytokines involved in regulating the immune response, and can reduce the survival, growth, proliferation, and migration of C6 cells, this flavonoid may be considered a potential antitumor drug for the adjuvant treatment of malignant gliomas. Copyright (C) 2016 Wolters Kluwer Health, Inc. All rights reserved.
Sunday, September 11, 2016 10:00 PM|EurekAlert! - Cancer Research News|Labels: brain cancer, glioma
(Karolinska Institutet) Glioblastomas exert an influence on the microglia, immune cells of the brain, which causes them to stimulate cancer growth rather than attacking it. In a study published in the journal Nature Immunology, an international research team led from Sweden's Karolinska Institutet now explains the molecular mechanisms behind this action.
Thursday, September 8, 2016 12:34 PM|Labussiere, M., Rahimian, A., Giry, M., Boisselier, B., Schmitt, Y., Polivka, M., Mokhtari, K., Delattre, J.-Y., Idbaih, A., Labreche, K., Alentorn, A., Sanson, M.|The Oncologist current issue|Labels: brain cancer, glioma

The 1p19q non-codeleted gliomas with IDH mutation, defined as "molecular astrocytomas," display frequent TP53 mutations and have an intermediate prognosis. We investigated the prognostic impact of copy number-neutral loss of heterozygosity (CNLOH) in 17p in this population.


We analyzed 793 gliomas (206 grade II, 377 grade III, and 210 grade IV) by single nucleotide polymorphism array and for TP53 mutations.


Homodisomy revealed by CNLOH was observed in 156 cases (19.7%). It was more frequent in astrocytomas and oligoastrocytomas (98/256, 38%) than oligodendrogliomas (28/327, 8.6%; p < .0001) or glioblastoma multiforme (30/210, 14.3%; p < .0001), tightly associated with TP53 mutation (69/71 vs. 20/79; p = 2 x 10–16), and mutually exclusive with 1p19q codeletion (1/156 vs. 249/556; p < .0001). In the group of IDH-mutated 1p19q non-codeleted gliomas, CNLOH 17p was associated with longer survival (86.3 vs. 46.2 months; p = .004), particularly in grade III gliomas (overall survival >100 vs. 37.9 months; p = .007). These data were confirmed in an independent dataset from the Cancer Genome Atlas.


CNLOH 17p is a prognostic marker and further refines the molecular classification of gliomas.

Implications for Practice:

Homodisomy of chromosome 17p (CNLOH 17p) is a frequent feature in IDH-mutated 1p19q non-codeleted gliomas (group 2). It is constantly associated with TP53 mutation. It was found, within this specific molecular group of gliomas (corresponding to molecular astrocytomas), that CNLOH 17p is associated with a much better outcome and may therefore represent an additional prognostic marker to refine the prognostic classification of gliomas.

Thursday, September 1, 2016 10:05 PM|Cherry, A. E., Haas, B. R., Naydenov, A. V., Fung, S., Xu, C., Swinney, K., Wagenbach, M., Freeling, J., Canton, D. A., Coy, J., Horne, E. A., Rickman, B., Vicente, J. J., Scott, J. D., Ho, R. J. Y., Liggitt, D., Wordeman, L., Stella, N.|Molecular Cancer Therapeutics current issue|Labels: brain cancer, glioma

Glioblastoma multiforme is a devastating and intractable type of cancer. Current antineoplastic drugs do not improve the median survival of patients diagnosed with glioblastoma multiforme beyond 14 to 15 months, in part because the blood–brain barrier is generally impermeable to many therapeutic agents. Drugs that target microtubules (MT) have shown remarkable efficacy in a variety of cancers, yet their use as glioblastoma multiforme treatments has also been hindered by the scarcity of brain-penetrant MT-targeting compounds. We have discovered a new alkylindole compound, ST-11, that acts directly on MTs and rapidly attenuates their rate of assembly. Accordingly, ST-11 arrests glioblastoma multiforme cells in prometaphase and triggers apoptosis. In vivo analyses reveal that unlike current antitubulin agents, ST-11 readily crosses the blood–brain barrier. Further investigation in a syngeneic orthotopic mouse model of glioblastoma multiforme shows that ST-11 activates caspase-3 in tumors to reduce tumor volume without overt toxicity. Thus, ST-11 represents the first member of a new class of brain-penetrant antitubulin therapeutic agents. Mol Cancer Ther; 15(9); 2018–29. ©2016 AACR.

Wednesday, August 31, 2016 10:05 PM|H.|JournalTOCs API - Clinical Cancer Research (27 articles)|Labels: Myc, brain cancer, glioma

Targeting Glycolysis for MYC-Driven Glioblastoma
Tateishi, K Iafrate, A. J, Ho, Q, Curry, W. T, Batchelor, T. T, Flaherty, K. T, Onozato, M. L, Lelic, N, Sundaram, S, Cahill, D. P, Chi, A. S, Wakimoto, H.
Clinical Cancer Research, Vol. 22, No. 17 (2016) pp. 4452 - 4465
Purpose: Deregulated Myc drives an oncogenic metabolic state, including pseudohypoxic glycolysis, adapted for the constitutive production of biomolecular precursors to feed rapid tumor cell growth. In glioblastoma, Myc facilitates renewal of the tumor-initiating cell reservoir contributing to tumor maintenance. We investigated whether targeting the Myc-driven metabolic state could be a selectively toxic therapeutic strategy for glioblastoma. Experimental Design: The glycolytic dependency of Myc-driven glioblastoma was tested using 13C metabolic flux analysis, glucose-limiting culture assays, and glycolysis inhibitors, including inhibitors of the NAD+ salvage enzyme nicotinamide phosphoribosyl-transferase (NAMPT), in MYC and MYCN shRNA knockdown and lentivirus overexpression systems and in patient-derived glioblastoma tumorspheres with and without MYC/MYCN amplification. The in vivo efficacy of glycolyic inhibition was tested using NAMPT inhibitors in MYCN-amplified patient-derived glioblastoma orthotopic xenograft mouse models. Results: Enforced Myc overexpression increased glucose flux and expression of glycolytic enzymes in glioblastoma cells. Myc and N-Myc knockdown and Myc overexpression systems demonstrated that Myc activity determined sensitivity and resistance to inhibition of glycolysis. Small-molecule inhibitors of glycolysis, particularly NAMPT inhibitors, were selectively toxic to MYC/MYCN&ndash;amplified patient-derived glioblastoma tumorspheres. NAMPT inhibitors were potently cytotoxic, inducing apoptosis and significantly extended the survival of mice bearing MYCN-amplified patient-derived glioblastoma orthotopic xenografts. Conclusions: Myc activation in glioblastoma generates a dependency on glycolysis and an addiction to metabolites required for glycolysis. Glycolytic inhibition via NAMPT inhibition represents a novel metabolically targeted therapeutic strategy for MYC or MYCN-amplified glioblastoma and potentially other cancers genetically driven by Myc. Clin Cancer Res; 22(17); 4452&ndash;65. &copy;2016 AACR.

Monday, August 29, 2016 6:00 PM|Hong-Hao Zhou|International Journal of Molecular Sciences|Labels: brain cancer, glioma
Emerging studies show that long noncoding RNAs (lncRNAs) have important roles in carcinogenesis. lncRNA ZEB1 antisense 1 (ZEB1-AS1) is a novel lncRNA, whose clinical significance, biological function, and underlying mechanism remains unclear in glioma. Here, we found that ZEB1-AS1 was highly expressed in glioma tissues, being closely related to clinical stage of glioma. Moreover, patients with high ZEB1-AS1 levels had poor prognoses, with the evidence provided by multivariate Cox regression analysis indicating that ZEB1-AS1 expression could serve as an independent prognostic factor in glioma patients. Functionally, silencing of ZEB1-AS1 could significantly inhibit cell proliferation, migration, and invasion, as well as promote apoptosis. Knockdown of ZEB1-AS1 significantly induced the G0/G1 phase arrest and correspondingly decreased the percentage of S phase cells. Further analysis indicated that ZEB1-AS1 could regulate the cell cycle by inhibiting the expression of G1/S transition key regulators, such as Cyclin D1 and CDK2. Furthermore, ZEB1-AS1 functioned as an important regulator of migration and invasion via activating epithelial to mesenchymal transition (EMT) through up-regulating the expression of ZEB1, MMP2, MMP9, N-cadherin, and Integrin-β1 as well as decreasing E-cadherin levels in the metastatic progression of glioma. Additionally, forced down-regulation of ZEB1-AS1 could dramatically promote apoptosis by increasing the expression level of Bax and reducing Bcl-2 expression in glioma. Taken together, our data suggest that ZEB1-AS1 may serve as a new prognostic biomarker and therapeutic target of glioma.
Friday, August 26, 2016 1:20 PM|Elsevier|JournalTOCs API - Biochemical and Biophysical Research Communications (50 articles)|Labels: brain cancer, glioma

Silencing Drp1 inhibits glioma cells proliferation and invasion by RHOA/ ROCK1 pathway

Biochemical and Biophysical Research Communications, Vol. , No. (2016) pp. -
Publication date: 16 September 2016 Source:Biochemical and Biophysical Research Communications, Volume 478, Issue 2 Author(s): Maojia Yin, Qin Lu, Xi Liu, Teng Wang, Ying Liu, Lifen Chen Backgrounds Dynamin-related protein 1 (Drp1) is a newly discovered therapeutic target for tumor initiation, migration, proliferation, and chemosensitivity. In the present study, we aimed to examine the level of expression and distribution of DRP1 in glioma tissues and explore the concrete mechanism of DRP1 played in glioma. Methods Expression of DRP1 in glioma tissues was determined by immunohistochemistry staining. The DRP1 gene was knocked down using small interfering RNA, and was overexpressed using plasmids in glioma cells. To assess changes in cell function, in vitro assays for invasion and growth were applied. Protein expression was tested by using Western-blot method. Variation of F-actin in cells was analyzed using immunofluorescence staining. Interactions between proteins were determined by co-immunoprecipitation. Results The protein expression levels of DRP1 were significantly increased in glioma tissues compared to the normal brain tissues. Down-regulation of DRP1 decreased cell proliferation and invasion, and inhibited the formation of pseudopodias and microvillis. Moreover, a possible link between DRP1 and RHOA was confirmed when interactions between these two proteins were observed in the cells. Conclusions Our results demonstrated that silencing DRP1 regulated the cytoskeleton remodeling through inhibiting RHOA/ROCK1 pathway, and thus decreased the proliferation and invasion of glioma cells.

Thursday, August 25, 2016 6:00 PM|Tao Jiang|International Journal of Molecular Sciences|Labels: brain cancer, glioma
The A disintegrin and metalloproteinase 9 (ADAM9) protein has been suggested to promote carcinoma invasion and appears to be overexpressed in various human cancers. However, its role has rarely been investigated in gliomas and, thus, in the current study we have evaluated ADAM9 expression in gliomas and examined the relevance of its expression in the prognosis of glioma patients. Clinical characteristics, RNA sequence data, and the case follow-ups were reviewed for 303 patients who had histological, confirmed gliomas. The ADAM9 expression between lower-grade glioma (LGG) and glioblastoma (GBM) patients was compared and its association with progression-free survival (PFS) and overall survival (OS) was assessed to evaluate its prognostic value. Our data suggested that GBM patients had significantly higher expression of ADAM9 in comparison to LGG patients (p &lt; 0.001, t-test). In addition, among the LGG patients, aggressive astrocytic tumors displayed significantly higher ADAM9 expression than oligodendroglial tumors (p &lt; 0.001, t-test). Moreover, high ADAM9 expression also correlated with poor clinical outcome (p &lt; 0.001 and p &lt; 0.001, log-rank test, for PFS and OS, respectively) in LGG patients. Further, multivariate analysis suggested ADAM9 expression to be an independent marker of poor survival (p = 0.002 and p = 0.003, for PFS and OS, respectively). These results suggest that ADAM9 mRNA expression is associated with tumor grade and histological type in gliomas and can serve as an independent prognostic factor, specifically in LGG patients.
Friday, August 19, 2016 10:45 AM|Calinescu, A. A., Yadav, V. N., Carballo, E., Kadiyala, P., Tran, D., Zamler, D., Doherty, R., Srikanth, M., Lowenstein, P. R., Castro, M. G.|Clinical Cancer Research Online First Articles|Labels: CXCRX, brain cancer, glioma

Purpose: One likely cause of treatment failure in glioblastoma is the persistence of glioma stem-like cells (GSLCs), highly resistant to therapies currently employed. We found that CXCL12 has highest expression in glioma cells derived from neural progenitor cells (NPCs). The development and molecular signature of NPC-derived GBMs were analyzed and the therapeutic effect of blocking CXCL12 was tested. Experimental Design: Tumors were induced by injecting DNA into the lateral ventricle of neonatal mice, using the Sleeping Beauty transposase method. Histology and expression of GSLC markers were analyzed during disease progression. Survival upon treatment with pharmacologic (Plerixafor) or genetic inhibition of CXCR4 was analyzed. Primary neurospheres were generated and analyzed for proliferation, apoptosis and expression of proteins regulating survival and cell cycle progression. Results: Tumors induced from NPCs display histological features of human GBM and express markers of GSLC. In vivo, inhibiting the CXCL12/CXCR4 signaling axis results in increased survival of tumor-bearing animals. In vitro, CXCR4 blockade induces apoptosis and inhibits cell cycle progression, downregulates molecules regulating survival and proliferation and also blocks the hypoxic-induction of HIF-1α and CXCL12. Exogenous administration of CXCL12 rescues the drug-induced decrease in proliferation. Conclusions: This study demonstrates that the CXCL12/CXCR4 axis operates in GBM cells under hypoxic stress via an autocrine positive feedback mechanism, which promotes survival and cell cycle progression. Our study brings new mechanistic insight and encourages further exploration of the use of drugs blocking CXCL12 as adjuvant agents to target hypoxia-induced GBM progression, prevent resistance to treatment and recurrence of the disease.

Sunday, August 14, 2016 10:05 PM|Seoane, J.|Clinical Cancer Research recent issues|Labels: brain cancer, glioma

One the most important challenges in the treatment of cancer is its evolving genomic intratumor heterogeneity. Tumors are composed of assortments of cells with subclonal genomic alterations that evolve following Darwinian selection. Glioblastoma (GBM) is a prototypical heterogeneous tumor and still little is known about how intratumor heterogeneity influences the progression of GBM and, most importantly, determines the response to treatments and tumor relapse. The study of the spatial and temporal genomic architecture of GBM is essential to understand the biology and improve the treatment of this dismal disease. Through the study of primary and relapsed tumors and patient-derived xenograft models (PDX) of GBM, we are studying the genomic subclones emerging after treatment since these subclones might be enriched in genomic alterations that confer a selective advantage and resistance to treatment. Putative genomic alterations involved in tumor resistance to treatment are further studied and validated through PDX models.

Citation Format: Joan Seoane. Patient-derived xenograft models in glioblastoma. [abstract]. In: Proceedings of the AACR Special Conference: Patient-Derived Cancer Models: Present and Future Applications from Basic Science to the Clinic; Feb 11-14, 2016; New Orleans, LA. Philadelphia (PA): AACR; Clin Cancer Res 2016;22(16_Suppl):Abstract nr IA16.

Sunday, August 14, 2016 10:05 PM|Ofek, P., Dromi, N., Yerushalmi, N., Kredo-Russo, S., Grossman, R., Ram, Z., Satchi-Fainaro, R.|Clinical Cancer Research recent issues|Labels: brain cancer, glioma

Glioblastoma multiforme is a very heterogeneous tumor, highly infiltrative, angiogenic and resistant to standard therapeutic intervention. Experimental models currently used in research are mostly based on cancer cell lines, which are grown in culture for many generations and have lost many essential biological characteristics. In consequence, the xenograft tumor models derived from those cells do not maintain genomic and phenotypic characteristics present in the original tumor. It is questionable whether these artificial preclinical models can serve as reliable platforms to select the lead candidate for a novel therapeutic approach.

We utilized miRNA expression patterns to evaluate the clinical relevance of some of the currently available experimental models of GBM, searching for similarities and differences in miRNA expression levels between freshly isolated tumors, patient-derived primary cells and GBM cell lines grown in culture. The study included 22 formalin-fixed paraffin-embedded (FFPE) tumors from glioblastoma resections. Those were divided into two groups of Short Term Survivors (STS, survived up to 3 months from initial diagnosis; n=12) and Long Term Survivors (LTS, survived more than 3 years from initial diagnosis; n=10).We further tested 6 patient-derived primary cells, and 5 ATCC human GBM cell lines widely used in preclinical research. Two of the cell lines included dormant and fast-growing variants previously developed in our laboratory to resemble LTS and STS phenotypes, respectively. Samples were loaded on custom microRNA (miR) arrays, including 2172 known miRNAs (miRBase 19).

We found several miRNAs that were upregulated in the STS samples while others exhibited higher expression levels in the LTS samples.

Both GBM cell lines and patient-derived primary cells exhibited a miRNA profile which was very different from patient samples. Brain miRNAs used as brain markers, such as hsa-miR-124-3p), show relatively low expression levels in both patient-derived primary cells and commercial cell lines but are highly expressed in tumors.

We concluded that GBM experimental models must be reevaluated and pre-clinical findings derived from long-established and commonly used in vitro and in vivo models should be further validated in patient-derived models that are more suitable to evaluate the potential clinical relevance of new therapeutics.

Citation Format: Paula Ofek, Nir Dromi, Noga Yerushalmi, Sharon Kredo-Russo, Rachel Grossman, Zvi Ram, Ronit Satchi-Fainaro. Patient-derived GBM tumors versus patient-derived primary cells and GBM cell lines: lessons from microRNA profiling. [abstract]. In: Proceedings of the AACR Special Conference: Patient-Derived Cancer Models: Present and Future Applications from Basic Science to the Clinic; Feb 11-14, 2016; New Orleans, LA. Philadelphia (PA): AACR; Clin Cancer Res 2016;22(16_Suppl):Abstract nr B05.

Sunday, August 14, 2016 10:05 PM|Han, T. J., Choi, E. J., Cho, B. J., Song, S. H., Paek, S. H., Kim, I. A.|Clinical Cancer Research recent issues|Labels: STAT, brain cancer, glioma

Background and purpose: Despite aggressive treatment with radiation therapy plus temozolomide (TMZ), the prognosis for glioblastoma remains poor. We investigated the potential of targeting signal transducer and activator of transcription-3 (STAT3) to improve the therapeutic outcome of glioblastoma.

Material and methods: We evaluated the preclinical potential of a STAT3 inhibitor, Cpd188 combined with temozolomide and radiation in vitro assays using two established glioblastoma cell lines (U251, U87) and two patients-derived glioblastoma cell lines (GBL12, GBL28) and in vivo studies using nude mice bearing intracranial U251 xenografts.

Results: Cpd188 potentiated the radiosensitizing effect of TMZ in U251 cell which has high levels of p-STAT3 expression. Increased radiosensitizing effects of TMZ were associated with impaired DNA damage repair, apoptosis and the reversion of epithelial-mesenchymal transition (EMT). Cpd188 delayed in vivo tumor growth both alone and in combination with radiation and TMZ. We also confirmed the radiosensitizing effect of Cpd188 of GBL28 cell which was originated from a patient with high level of STAT3 expression and unmethylated MGMT.

Conclusion: Targeting STAT3 using Cpd188 could be a viable therapeutic approach to improve the outcome of current standard therapy for glioblastoma patients having high p-STAT3 expression regardless of MGMT methylation status.

*Work supported by the grant (#2013R1A1A2074531) from the Ministry of Science, ICT & Future Planning to In Ah Kim

Citation Format: Tae Jin Han, Eun Jung Choi, Bong Jun Cho, Sang Hyuk Song, Sun Ha Paek, In Ah Kim{Authors}. Inhibition of STAT3 enhances the radiosensitizing effect of Temozolomide in vitro and in vivo: Validation using patient-derived glioblastoma model. [abstract]. In: Proceedings of the AACR Special Conference: Patient-Derived Cancer Models: Present and Future Applications from Basic Science to the Clinic; Feb 11-14, 2016; New Orleans, LA. Philadelphia (PA): AACR; Clin Cancer Res 2016;22(16_Suppl):Abstract nr B46.

Friday, August 12, 2016 12:58 PM|Reinartz, R., Wang, S., Kebir, S., Silver, D. J., Anja, W., Zheng, T., Küpper, M., Rauschenbach, L., Fimmers, R., Shepherd, T., Trageser, D., Till, A., Schäfer, N., Glas, M., Hillmer, A. M., Cichon, S., Smith, A., Pietsch, T., Liu, Y., Reynolds, B. A., Yachnis, A. T., Pincus, D. W., Simon, M., Brüstle, O., Steindler, D. A., Scheffler, B.|Clinical Cancer Research Online First Articles|Labels: brain cancer, glioma

Purpose: Investigation of clonal heterogeneity may be key to understanding mechanisms of therapeutic failure in human cancer. However, little is known on the consequences of therapeutic intervention on the clonal composition of solid tumors. Experimental Design: Here, we used 33 single cell-derived subclones generated from five clinical glioblastoma specimens for exploring intra- and inter-individual spectra of drug resistance profiles in vitro. In a personalized setting, we explored whether differences in pharmacological sensitivity among subclones could be employed to predict drug-dependent changes to the clonal composition of tumors. Results: Subclones from individual tumors exhibited a remarkable heterogeneity of drug resistance to a library of potential anti-glioblastoma compounds. A more comprehensive intra-tumoral analysis revealed that stable genetic and phenotypic characteristics of co-existing subclones could be correlated with distinct drug sensitivity profiles. The data obtained from differential drug response analysis could be employed to predict clonal population shifts within the naïve parental tumor in vitro and in orthotopic xenografts. Furthermore, the value of pharmacological profiles could be shown for establishing rational strategies for individualized secondary lines of treatment. Conclusions: Our data provide a previously unrecognized strategy for revealing functional consequences of intra-tumor heterogeneity by enabling predictive modeling of treatment-related subclone dynamics in human glioblastoma.

Wednesday, August 3, 2016 3:58 AM|Takahiro Domoto, Ilya V. Pyko, Takuya Furuta, Katsuyoshi Miyashita, Masahiro Uehara, Takeo Shimasaki, Mitsutoshi Nakada, Toshinari Minamoto|Cancer Science|Labels: brain cancer, pancreatic cancer, glioma
Tumor cell invasion and resistance to therapy are the most intractable biological characteristics of cancer and therefore the most challenging for current cancer research and treatment paradigms. Refractory cancers, including pancreatic cancer and glioblastoma, show an inextricable association between the highly invasive behavior of tumor cells and their resistance to chemo-, radio- and targeted therapies. These aggressive properties of cancer share distinct cellular pathways that are connected to each other by several molecular hubs. There is increasing evidence to show that glycogen synthase kinase (GSK)-3β is aberrantly activated in various cancer types and this has emerged as a potential therapeutic target. In many but not all cancer types, aberrant GSK3β sustains the survival, immortalization, proliferation and invasion of tumor cells, while also rendering them insensitive or resistant to chemotherapeutic agents and radiation. Here we review studies that describe associations between therapeutic stimuli/resistance and the induction of pro-invasive phenotypes in various cancer types. Such cancers are largely responsive to treatment that targets GSK3β. This review focuses on role of GSK3β as a molecular hub that connects pathways responsible for tumor invasion and resistance to therapy, thus highlighting its potential as a major cancer therapeutic target. We also discuss the putative involvement of GSK3β in determining tumor cell stemness that underpins both tumor invasion and therapy resistance, leading to intractable and refractory cancer with dismal patient outcomes. This article is protected by copyright. All rights reserved.
Monday, August 1, 2016 10:05 PM|Unknown Author|Cancer Discovery recent issues|Labels: brain cancer, glioma

Dopamine receptor D4 (DRD4) is a potential therapeutic target in glioblastoma stem cells.

Sunday, July 31, 2016 10:05 PM|Lun, X., Wells, J. C., Grinshtein, N., King, J. C., Hao, X., Dang, N.-H., Wang, X., Aman, A., Uehling, D., Datti, A., Wrana, J. L., Easaw, J. C., Luchman, A., Weiss, S., Cairncross, J. G., Kaplan, D. R., Robbins, S. M., Senger, D. L.|Clinical Cancer Research recent issues|Labels: brain cancer, glioma

Purpose: Glioblastoma is one of the most lethal cancers in humans, and with existing therapy, survival remains at 14.6 months. Current barriers to successful treatment include their infiltrative behavior, extensive tumor heterogeneity, and the presence of a stem-like population of cells, termed brain tumor–initiating cells (BTIC) that confer resistance to conventional therapies.

Experimental Design: To develop therapeutic strategies that target BTICs, we focused on a repurposing approach that explored already-marketed (clinically approved) drugs for therapeutic potential against patient-derived BTICs that encompass the genetic and phenotypic heterogeneity of glioblastoma observed clinically.

Results: Using a high-throughput in vitro drug screen, we found that montelukast, clioquinol, and disulfiram (DSF) were cytotoxic against a large panel of patient-derived BTICs. Of these compounds, disulfiram, an off-patent drug previously used to treat alcoholism, in the presence of a copper supplement, showed low nanomolar efficacy in BTICs including those resistant to temozolomide and the highly infiltrative quiescent stem-like population. Low dose DSF-Cu significantly augmented temozolomide activity in vitro, and importantly, prolonged in vivo survival in patient-derived BTIC models established from both newly diagnosed and recurrent tumors. Moreover, we found that in addition to acting as a potent proteasome inhibitor, DSF-Cu functionally impairs DNA repair pathways and enhances the effects of DNA alkylating agents and radiation. These observations suggest that DSF-Cu inhibits proteasome activity and augments the therapeutic effects of DNA-damaging agents (temozolomide and radiation).

Conclusions: DSF-Cu should be considered as an adjuvant therapy for the treatment of patients with glioblastoma in both newly diagnosed and recurrent settings. Clin Cancer Res; 22(15); 3860–75. ©2016 AACR.

Thursday, July 28, 2016 7:56 AM|Barnes, J. M., Miroshnikova, Y. A., Tung, J. C., Bainer, R. O., Weaver, V. M.|Cancer Research recent issues|Labels: brain cancer, glioma
Glioblastoma multiforme (GBM) is a malignant brain tumor whose progression is associated with rampant extracellular matrix (ECM) remodeling. We recently found that ECM stiffness correlates with poor survival in human GBM specimens. Glycoproteins are the major constituent of normal brain ECM and many are overexpressed in brain tumors, yet the interplay between glycoproteins and mechanical signaling in GBM pathogenesis remains poorly understood. Here, we show that bulky glycoproteins and sugar-binding proteins are broadly upregulated in GBM relative to lower grade gliomas. Further, these genes are overexpressed in the mesenchymal (Mes) relative to the proneural (Pro) GBM subclass, the former of which is associated with treatment resistance and relapse. We took a specific interest in the hyaluronic acid (HA)-producing enzyme, HAS2, and the galactoside-binding lectin galectin-1 (Gal1) due to their ability to modulate tissue structure and rheology. Using mouse models of human GBM we showed that Mes tumors are enriched in HA and fibronectin, coincident with elevated ECM stiffness and mechanical signaling. These data suggest the possibility that aberrant glycoprotein expression drives GBM aggression through enhanced mechanical signaling resulting from tissue stiffening. Consistent with this hypothesis, by elevating mechanical signaling in Pro GBMs we induce a robust Mes-like transition and we see the opposite when reducing Gal1 expression or HA content in Mes tumors. Our data provides evidence of a feed-forward mechanism whereby mechanical signaling drives Gal1 and HA production which reinforce ECM stiffness, thus sustaining pro-tumorigenic mechanical signaling.This abstract is also presented as Poster A21.Citation Format: J Matthew Barnes, Yekaterina A. Miroshnikova, Jason C. Tung, Russel O. Bainer, Valerie M. Weaver. A glycoprotein-mediated mechanical switch promotes glioma aggression. [abstract]. In: Proceedings of the AACR Special Conference: Function of Tumor Microenvironment in Cancer Progression; 2016 Jan 7–10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2016;76(15 Suppl):Abstract nr PR10.

Optic pathway glioma (OPG) is a rare neoplasm and a defining feature of neurofibromatosis type 1 (NF1), a tumor suppressor genetic disorder. OPG predominantly arises during childhood. In contrast to sporadic OPG, this neoplasm frequently appears to show a more favorable course. Outcome appears to depend on localization of tumor; however, the correlation of imaging findings and visual acuity is in general low. Treatment for symptomatic OPG is not well standardized. Furthermore, determination of visual acuity as the most important parameter of follow-up control is often difficult to determine, particularly in children. Focal abnormal signal intensity (FASI) is a characteristic finding on magnetic resonance imaging (MRI) of NF1 patients. The aim of this study was to evaluate clinical and imaging findings of NF1 patients affected with OPG. Patients and Methods: Data of 925 NF1 patients with appropriate MRI cranial sectional images (N=1,948) were evaluated. A further 50 patients with cranial computed tomograms were included in the study. We compared imaging and clinical findings with respect to localization of OPG. Furthermore, we compared follow-up in treated individuals to those who were only regularly re-examined. The presence of FASI on MRI was determined and correlated to the occurrence of OPG. Dodge classification was applied to categorize OPG location. Results: OPG was diagnosed in 134 patients. The mean age of patients with symptomatic OPG was 7.6 years (n=57, 42.5%) and 11.6 years (n=77, 57.5%) in asymptomatic patients. The female to male ratio was about 1.1:1. In 48 symptomatic patients, the findings of initial ophthalmological investigations were available. In symptomatic patients, reduced visual acuity was the predominant finding. Strabismus (25%), exophthalmos (22.9%) and amblyopia (20.8%) were most frequently noticed, followed by endrocrinological abnormalities (14.6%). However, these findings did not differ between patients who were treated or who were subjected to a ‘wait-and-see’ policy. We could not verify an effect of therapy on vision in patients treated for OPG compared to symptomatic patients without treatment. OPG affecting the total optic pathway was more frequently diagnosed in symptomatic patients. FASI did not correlate with functional OPG status. Conclusion: OPG in NF1 is symptomatic in slightly less than 50% of affected individuals. This neurological finding may show a wide range of symptoms. At present, no established treatment protocol emerges from the history of the patients of this study and also from the literature. Although the onset of symptomatic OPG is strongly associated with early childhood, late onset of symptomatic OPG is a feature of adult NF1. Research for association of FASI to neurological findings in these patients should be based on other issues than association with OPG.

Wednesday, July 27, 2016 11:11 AM|PIRTOLI, L., BELMONTE, G., TOSCANO, M., TINI, P., MIRACCO, C.|Anticancer Research recent issues|Labels: brain cancer, glioma

Background: Glioblastoma (GB) recurrences are rarely removed, therefore, tissue modifications induced by radiotherapy, and temozolomide chemotherapy are scarcely known. Nuclear cyclin D1 is associated with GB progression and resistance to therapy. We previously found that the expression of autophagic protein beclin-1 is a major determinant of prognosis in GB. Patients and Methods: In 31 patients with primary GB and their recurrences, we investigated the protein expression of cyclin D1 and beclin-1, before and after radiotherapy-temozolomide therapy by immunohistochemistry. Results: Most (20/31) primary GBs were negative for nuclear cyclin D1, and highly expressed beclin-1. In their recurrences, cytoplasmic cyclin D1 positivity was observable, which co-localized with beclin-1. Eleven primary GBs instead exhibited low beclin-1 expression and were positive for nuclear cyclin D1; three of their recurrences exhibited an increase of beclin-1, which co-localized with cyclin D1 in the cytoplasm. Conclusion: Our results suggest therapy-induced degradation of cyclin D1 via autophagy.

Monday, July 25, 2016 3:00 PM|Current Pharmaceutical Design|Current Pharmaceutical Design via|Comments|Labels: brain cancer, glioma
Authors: Humle N, Johnsen KB, Arendt GA, Nielsen RP, Moos T, Thomsen LB Abstract This review presents the present-day literature on the anatomy and physiological mechanisms of the blood-brain barrier and the problematic of cerebral drug delivery in relation to malignant brain tumors. First step in treatment of malignant brain tumors is resection, but there is a high risk of single remnant infiltrative tumor cells in the outer zone of the brain tumor. These infiltrative single-cells will be supplied by capillaries with an intact BBB as opposed to the partly leaky BBB found in the tumor tissue before resection. Even though BBB penetrance of a chemotherapeutic agent is considered irrelevant the limited success rate for chemotherapeutic treatability of GBM tumors indicate otherwise. Th...
Tuesday, July 19, 2016 9:21 AM|Tateishi, K., Iafrate, A. J., Ho, Q., Curry, W. T., Batchelor, T. T., Flaherty, K. T., Onozato, M. L., Lelic, N., Sundaram, S., Cahill, D. P., Chi, A. S., Wakimoto, H.|Clinical Cancer Research Online First Articles|Labels: Myc, brain cancer, glioma

Purpose: Deregulated Myc drives an oncogenic metabolic state, including pseudohypoxic glycolysis, adapted for the constitutive production of biomolecular precursors to feed rapid tumor cell growth. In glioblastoma, Myc facilitates renewal of the tumor-initiating cell reservoir contributing to tumor maintenance. We investigated whether targeting the Myc-driven metabolic state could be a selectively toxic therapeutic strategy for glioblastoma.

Experimental Design: The glycolytic dependency of Myc-driven glioblastoma was tested using 13C metabolic flux analysis, glucose-limiting culture assays, and glycolysis inhibitors, including inhibitors of the NAD+ salvage enzyme nicotinamide phosphoribosyl-transferase (NAMPT), in MYC and MYCN shRNA knockdown and lentivirus overexpression systems and in patient-derived glioblastoma tumorspheres with and without MYC/MYCN amplification. The in vivo efficacy of glycolyic inhibition was tested using NAMPT inhibitors in MYCN-amplified patient-derived glioblastoma orthotopic xenograft mouse models.

Results: Enforced Myc overexpression increased glucose flux and expression of glycolytic enzymes in glioblastoma cells. Myc and N-Myc knockdown and Myc overexpression systems demonstrated that Myc activity determined sensitivity and resistance to inhibition of glycolysis. Small-molecule inhibitors of glycolysis, particularly NAMPT inhibitors, were selectively toxic to MYC/MYCN–amplified patient-derived glioblastoma tumorspheres. NAMPT inhibitors were potently cytotoxic, inducing apoptosis and significantly extended the survival of mice bearing MYCN-amplified patient-derived glioblastoma orthotopic xenografts.

Conclusion: Myc activation in glioblastoma generates a dependency on glycolysis and an addiction to metabolites required for glycolysis. Glycolytic inhibition via NAMPT inhibition represents a novel metabolically targeted therapeutic strategy for MYC or MYCN-amplified glioblastoma and potentially other cancers genetically driven by Myc. Clin Cancer Res; 1–14. ©2016 AACR.

Wednesday, June 29, 2016 9:30 AM|Kim, J. E., Patel, M. A., Mangraviti, A., Kim, E. S., Theodros, D., Velarde, E., Liu, A., Sankey, E., Tam, A., Xu, H., Mathios, D., Jackson, C. M., Harris-Bookman, S., Garzon-Muvdi, T., Sheu, M., Martin, A. M., Tyler, B. M., Tran, P. T., Ye, X., Olivi, A., Taube, J. M., Burger, P. C., Drake, C. G., Brem, H., Pardoll, D. M., Lim, M.|Clinical Cancer Research Online First Articles|Labels: PD-1/PD-L1, brain cancer, glioma

Introduction: Checkpoint molecules like programmed death-1 (PD-1) and T cell immunoglobulin mucin-3 (TIM-3) are negative immune regulators that may be upregulated in the setting of glioblastoma multiforme (GBM). Combined PD-1 blockade and stereotactic radiosurgery (SRS) have been shown to improve antitumor immunity and produce long-term survivors in a murine glioma model (1) . However, tumor-infiltrating lymphocytes (TILs) can express multiple checkpoints, and expression of {greater than or equal to}2 checkpoints corresponds to a more exhausted T cell phenotype (2) . We investigate TIM-3 expression in a glioma model and the antitumor efficacy of TIM-3 blockade alone and in combination with anti-PD-1 and SRS. Methods: C57BL/6 mice were implanted with murine glioma cell line GL261-luc2 and randomized into 8 treatment arms: (1) control, (2) SRS, (3) anti-PD-1 antibody, (4) anti-TIM-3 antibody, (5) anti-PD-1+SRS, (6) anti-TIM-3+SRS, (7) anti-PD-1+anti-TIM-3, and (8) anti-PD-1+anti-TIM-3+SRS. Survival and immune activation were assessed. Results: Dual therapy with anti-TIM-3 antibody+SRS or anti-TIM-3+anti-PD-1 improved survival compared to anti-TIM-3 antibody alone. Triple therapy resulted in 100% OS (p<0.05), a significant improvement compared to other arms. Long-term survivors demonstrated increased immune cell infiltration and activity, and immune memory. Lastly, positive staining for TIM-3 was detected in 7/8 human GBM samples. Conclusions: This is the first preclinical investigation on the effects of dual PD-1 and TIM-3 blockade with radiation. We also demonstrate the presence of TIM-3 in human GBM and provide preclinical evidence for a novel treatment combination that can potentially result in long-term glioma survival and constitutes a novel immunotherapeutic strategy for the treatment of GBM.

Monday, June 27, 2016 10:52 AM|TASAKI, T., FUJITA, M., OKUDA, T., YONESHIGE, A., NAKATA, S., YAMASHITA, K., YOSHIOKA, H., IZUMOTO, S., KATO, A.|Anticancer Research recent issues|Labels: MET, brain cancer, glioma

Background: Glioblastoma multiforme (GBM) is the most frequent and the most malignant tumor among adult brain tumors. Previous reports led us to hypothesize that the proto-oncogene mesenchymal–epithelial transition (MET) expressed in glioma stem cell-like cells (GSCs) would be a potent therapeutic target for GBM. Patients and Methods: To address this question, we analyzed 113 original samples of tumors from patients based on immunohistochemistry. During this process, we were able to establish GSC lines from patients with GBM that were MET-positive and MET-negative. Using these cells, we tested the therapeutic impact of a MET inhibitor, crizotinib, both in vitro and in vivo. Results: Patients with MET-positive GBM exhibited poor survival. GSC-based experiments revealed that treatment with crizotinib, both in vitro and in vivo, exhibited therapeutic efficacy particularly against MET-positive GSCs. Conclusion: Based on these findings, we conclude that MET expressed in GSCs might be a potent therapeutic target for GBM.

Monday, June 27, 2016 10:52 AM|WANG, T., PICKARD, A. J., GALLO, J. M.|Anticancer Research recent issues|Labels: brain cancer, glioma

Background/Aim: The alkylating agent, temozolomide (TMZ), is considered the standard-of-care for high-grade astrocytomas –known as glioblastoma multiforme (GBM)– an aggressive type of tumor with poor prognosis. The therapeutic benefit of TMZ is attributed to formation of DNA adducts involving the methylation of purine bases in DNA. We investigated the effects of TMZ on arginine and lysine amino acids, histone H3 peptides and histone H3 proteins. Materials and Methods: Chemical modification of amino acids, histone H3 peptide and protein by TMZ was performed in phosphate buffer at physiological pH. The reaction products were examined by mass spectrometry and western blot analysis. Results: Our results showed that TMZ following conversion to a methylating cation, can methylate histone H3 peptide and histone H3 protein, suggesting that TMZ exerts its anticancer activity not only through its interaction with DNA, but also through alterations of protein post-translational modifications. Conclusion: The possibility that TMZ can methylate histones involved with epigenetic regulation of protein indicates a potentially unique mechanism of action. The study will contribute to the understanding the anticancer activity of TMZ in order to develop novel targeted molecular strategies to advance the cancer treatment.

Tuesday, June 7, 2016 5:38 PM|Onclive Brain Cancer Articles|Labels: PD-1/PD-L1, VEGF, brain cancer, clinical trial, glioma
An immunotherapy/antiangiogenesis combination proved to be safe and tolerable for patients with recurrent glioblastoma, preliminary data from an ongoing trial showed.
Sunday, June 5, 2016 3:58 PM|Onclive Brain Cancer Articles|Labels: VEGF, brain cancer, clinical trial, glioma
A novel antiangiogenic gene therapy, added to bevacizumab, led to significantly better overall survival in recurrent glioblastoma multiforme compared with historical patients treated with bevacizumab alone, a small phase II trial showed.
Sunday, June 5, 2016 11:03 AM|Onclive Brain Cancer Articles|Labels: brain cancer, glioma
Adding temozolomide to short-course radiotherapy after surgery boosted overall survival by nearly 2 months, bringing 1-year survival rates up from 22.2% to 37.8% for elderly patients with glioblastoma.
Saturday, June 4, 2016 4:07 PM|Onclive Brain Cancer Articles|Labels: brain cancer, clinical trial, glioma
Single-agent nivolumab demonstrated encouraging signs of activity with a mild adverse event profile for patients with recurrent glioblastoma multiforme.
Friday, June 3, 2016 5:09 PM|Onclive Brain Cancer Articles|Labels: brain cancer, clinical trial, glioma
Results from a phase III trial investigating the benefit of adjuvant temozolomide in combination with radiation therapy has the potential to be practice changing for a rare type of brain cancer.
Thursday, June 2, 2016 10:05 PM|Unknown Author|Cancer Discovery recent issues|Labels: brain cancer, glioma

Researchers have shown that glioblastomas can develop resistance to a drug by rewiring their signaling networks to counteract its effects. Combining drugs that target two network changes produced remissions in mice implanted with human glioblastomas.

Monday, May 16, 2016 2:20 AM|Onclive Brain Cancer Articles|Labels: brain cancer, glioma
The recombinant oncolytic poliovirus PVS-RIPO has received breakthrough therapy designation from the FDA as a potential treatment for patients with recurrent glioblastoma multiforme.
Thursday, April 28, 2016 7:50 AM|Behling, K., Maguire, W. F., Puebla, J. C. L., Sprinkle, S. R., Ruggiero, A., O'Donoghue, J., Gutin, P. H., Scheinberg, D. A., McDevitt, M. R.|JNM Ahead of Print|Labels: brain cancer, glioma

Rationale: Glioblastoma (GBM) is characterized by an aggressive and aberrant vascular network that promotes tumor progression and hinders effective treatment; the median survival is 16 months despite standard-of-care therapies. There is a need to improve therapeutic options for this disease. We hypothesized that antibody targeting of the vascular endothelium (VE) of glioblastoma with cytotoxic short-range, high-energy alpha particles would be an effective therapeutic approach. Methods: E4G10, an antibody directed at an epitope of monomeric VE cadherin, is expressed in tumor neovasculature and on endothelial progenitor cells in the bone marrow. E4G10 was labeled with alpha particle emitting 225Actinium (225Ac). Pharmacokinetic studies investigated the tissue distribution and blood clearance of the 225Ac-E4G10 radioimmunoconstruct in a transgenic XFM mouse model of high-grade glioblastoma. Histological analysis was used to demonstrate local therapeutic effects in treated brain tumor sections. Radioimmunotherapy with 225Ac-E4G10 was performed in XFM mice to assess overall survival alone and in combination with temozolomide, the standard-of-care chemotherapeutic agent. Results: 225Ac-E4G10 was found to accumulate in tissues expressing the target antigen. Anti-vascular alpha-particle therapy of glioblastoma in the transgenic XFM model resulted in significantly improved survival compared to controls and potent control of tumor growth. Adding the chemotherapeutic temozolomide to the treatment increased survival to 30 days (versus 9 days for vehicle treated animals). Histological analyses showed a remodeled GBM vascular microenvironment. Conclusion: Targeted alpha-particle anti-vascular therapy is shown for the first time to be effective in increasing overall survival in a solid tumor in a clinically relevant transgenic GBM mouse model.

CONCLUSIONSChildren with NF1 tolerated CV well and had tumor response rates and EFS that were superior to those for children without NF1. Cancer 2016. © 2016 American Cancer Society. (Source: Cancer)
CONCLUSIONSThe course of PLGG is associated with excellent long‐term survival, but this is hampered by increased delayed mortality in patients receiving upfront radiotherapy. These observations should be considered when treatment options are being weighed for these patients. Cancer 2016. © 2016 American Cancer Society. (Source: Cancer)
Monday, February 29, 2016 4:00 PM|Acta Biochimica et Biophysica Sinica|MedWorm: Cancer Therapy|Comments|Labels: brain cancer, biomarker diagnostic, glioma
Authors: Zheng J, Dong W, Zhang J, Li G, Gong H Abstract Y box protein 1 (YB-1) is a multifunctional cellular protein expressed in various cancers, and is a potential target in cancer therapy. Although there is evidence showing that YB-1 plays a role in human cancers, the clinical significance of YB-1 expression in glioma has not been established. In the present study, we investigated the YB-1 level in glioma tumors and analyzed the relationship between the YB-1 level and the grade of malignant glioma, with the aim of providing new ideas for the diagnosis and treatment of gliomas in clinical and basic research settings. A total of 108 patients, comprising 14, 31, 30, and 33 with gliomas of Grades I, II, III, and IV, respectively, were included in this study. The mRNA and protein le...

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Thursday, January 14, 2016 4:00 PM|Molecular Cancer Research|MedWorm: Cancer Therapy|Comments|Labels: mTOR, brain cancer, glioma
Aerobic glycolysis (the Warburg effect), first recognized almost a century ago, by Otto Warburg is a core hallmark of cancer. The Warburg effect describes a switch in glucose metabolism from oxidative phosphorylation to glycolysis. Recently links have been established between the oncogenic pathways that drive tumorigenesis and the mechanistic basis of tumor cell metabolism. The kinase mTOR is a major driver of tumor metabolism and proliferation of cancer cells, acts downstream of numerous oncogenic pathways. Several drugs targeting the mTOR pathway are being developed, however the most common drug rapamycin does not inhibit mTOR complex-2. Therefore in the current study, we examined the potential benefit of MLN0128, a novel potent mTOR ATP competitive inhibitor, as a therapeutic strategy f...
Tuesday, January 12, 2016 9:00 PM|EurekAlert! - Cancer|MedWorm: Cancer Therapy|Comments|Labels: brain cancer, glioma
(The Translational Genomics Research Institute) The Translational Genomics Research Institute (TGen) has identified a protein called SGEF that promotes the survival of glioblastoma tumor cells and helps the cancer invade brain tissue. TGen researchers identified SGEF as a target for new brain cancer therapies in a study published today by Molecular Cancer Research, a journal of the American Association for Cancer Research, the world's largest professional organization dedicated to advancing cancer research. (Source: EurekAlert! - Cancer)
Thursday, October 22, 2015 6:00 PM|Jer-Yen Yang|Cancers|Labels: Hh/SMO, brain cancer, childhood cancer, glioma
Medulloblastoma (MB), a primitive neuroectomal tumor of the cerebellum, is the most common malignant pediatric brain tumor. The cause of MB is largely unknown, but aberrant activation of Hedgehog (Hh) pathway is responsible for ~30% of MB. Despite aggressive treatment with surgical resection, radiation and chemotherapy, 70%–80% of pediatric medulloblastoma cases can be controlled, but most treated patients suffer devastating side effects. Therefore, developing a new effective treatment strategy is urgently needed. Hh signaling controls transcription of target genes by regulating activities of the three Glioma-associated oncogene (Gli1-3) transcription factors. In this review, we will focus on current clinical treatment options of MB and discuss mechanisms of drug resistance. In addition, we will describe current known molecular pathways which crosstalk with the Hedgehog pathway both in the context of medulloblastoma and non-medulloblastoma cancer development. Finally, we will introduce post-translational modifications that modulate Gli1 activity and summarize the positive and negative regulations of the Hh/Gli1 pathway. Towards developing novel combination therapies for medulloblastoma treatment, current information on interacting pathways and direct regulation of Hh signaling should prove critical