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Volume 1 (7). September 2013.

GLIOMAS.ORG

NEWSLETTER

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Volume 1 (7), September 2013.

www.gliomas.org

GLIOMAS.ORG NEWSLETTERSis a short electronic

newsletter periodically released by e-mail as a PDF file to sub-

scribers who want to keep updated on the latest advances on

glioma research including but not limited to:

DRUGS & CHEMOTHERAPY

NEURORADIOLOGY

NEUROIMAGING

NEUROSURGERY

NEUROPHARMACOLOGY

NANOMEDICINE

GLIOMA BIOLOGY

CLINICAL STUDIES related to the diagnosis, treatment and

prognosis of glioma patients.

Each issue of GLIOMAS NEWSLETTERS is the result of a broad

screening of the literature in free (e.g. pubmed) or subscription

based (e.g. ISI) databases and journals. Interaction with the

industry and academic institutions guarantee the early release

of relevant information for patients and professionals.

The highlights of important studies are briefly summarized in a

friendly medical language. Each summary is convenient cited

(Reference) at the bottom of the summary to allow anyone

interested to quickly find the original source.

GLIOMAS.ORG.

An International Consortium

Mission: To speed research ingliomas.

ACTIVITIES:

Research

Education

Communication

Lates updates

Patient support

Conference Meetings

www.gliomas.org

New issues of GLIOMAS.ORG NEWSLETTERS are re-

leased to subscribers periodically by e-mail. Since October2013, all issues are posted online in www.gliomas.org/nl and

can be freely distributed by any media. We encourage profes-

sionals, clinics and other institutions to print and distribute our

newsletter to their staff and patients.

IN THIS ISSUE

IMAGES IN GLIOMAS RESEARCH: - Resection probability maps for right-sided gliomasANNOUNCEMENTS: I Brain Tumors: Biology & Therapy (BTBT) MeetingEXPERIMENTAL CHEMOTHERAPY: - Optimization of the route of platinum drugs administration to optimize the concomitant treatment with radiother-

apy for glioblastoma implanted in the Fischer rat brain.

- Efficient induction of differentiation and growth inhibition in IDH1 mutant glioma cells by the DNMT Inhibitor DecitabineGLIOMA STEM CELL AS THERAPEUTIC TARGET: APO010, A Synthetic Hexameric CD95 Ligand, Induces Death of Human Glioblastoma Stem-likeCells.TUMOR BIOLOGY: - An EGFR wild type-EGFRvIII-HB-EGF feed-forward loop regulates the activation of EGFRvIII

- Tumor progression and transformation of low-grade glial tumors associated with pregnancy.NATURAL PRODUCTS: Punicalagin induces apoptotic and autophagic cell deathFROM THE INDUSTRY: to-BBB Receives IND Approval for Novel Brain Cancer Drug, 2B3-101

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IMAGES IN GLIOMAS RESEARCH

BACKGROUND: Intraoperative brain stimulation mapping reduces permanent postoperative deficits and extends tumor removal in resec-

tive surgery for glioma patients. Successful functional mapping is assumed to depend on the surgical team's expertise. In this study,

glioma resection results are quantified and compared using a novel approach, so-called resection probability maps (RPM), exemplified by

a surgical team comparison, here with long and short experience in mapping. METHODS: Adult patients with glioma were included by

two centers with two and fifteen years of mapping experience. Resective surgery was targeted at non-enhanced MRI extension and was

limited by functional boundaries. Neurological outcome was compared. To compare resection results, we applied RPMs to quantify and

compare the resection probability throughout the brain at 1 mm resolution. Considerations for spatial dependence and multiple compari-

sons were taken into account. RESULTS: The senior surgical team contributed 56, and the junior team 52 patients. The patient cohorts

were comparable in age, preoperative tumor volume, lateralization, and lobe localization. Neurological outcome was similar between

teams. The resection probability on the RPMs was very similar, with none (0%) of 703,967 voxels in left-sided tumors being differentially

resected, and 124 (0.02%) of 644,153 voxels in right-sided tumors.CONCLUSION: RPMs provide a quantitative volumetric method to com-

pare resection results, which we present as standard for quality assessment of resective glioma surgery because brain location bias is

avoided. Stimulation mapping is a robust surgical technique, because the neurological outcome and functional-based resection results

using stimulation mapping are independent of surgical experience, supporting wider implementation

Resection probability maps for right-sided gliomas. Results comparing (A) the junior surgical team, n = 29, and (B) the senior surgicalteam, n = 29, are shown superimposed on standard brain space (MNI152). A probability of 0 (red) represents locations where tumor was never resected, anda probability of 1 (green) represents locations where tumor was resected in all patients. An intermediate probability (yellow) represents locations where

glioma was removed in a subset of patients. (C) Relative differences in probability of resection as log odds ratio. (D) The adjusted p-value map adjusted bythe empirical null-distribution to address spatial dependency of voxels. Values less than 0.15 are plotted in shades of red. (E) The q-value map to addressmultiple testing. Values below 0.2 are plotted in shades of red, values between 0.2 and 0.8 in shades of blue. (F) Differences in probability of resection as

log odds ratio for voxels with a q-value less than 0.2 demonstrate similar resection results between the two patient cohorts. Results are superimposed on atransversal section at z = 0 of MNI152. See Movie S2 for all transversal sections. doi:10.1371/journal.pone.0073353.g003

De Witt Hamer PC, Hendriks EJ, Mandonnet E, Barkhof F, Zwinderman AH, Duffau H. Resection Probability Maps for Quality Assessment ofGliomaSurgery without Brain Location Bias. PLoS One. 2013 Sep 6;8(9):e73353. doi: 10.1371/journal.pone.0073353. PMID: 24039922

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ANNOUNCEMENTS FROM GLIOMAS.ORG

www.gliomas.org is organizing the I Brain Tumors: Biology and

Therapy (BTBT) meeting in Stockholm, Sweden (June 12-13,

2014). Several experts from Europe and United States have

confirmed their participation as speakers. The meeting is also

open to supporting groups for glioma patiens and fundraisers.

As part of the meeting, an optional workshop IntegratedApproach of Preclinical Anticancer Drug Screening for

Brain Tumors is scheduled for June 15.

Website: www.gliomas.org/nom

EXPERIMENTAL CHEMOTHERAPY

Optimization of the route of platinum drugs administration to

optimize the concomitant treatment with radiotherapy for

glioblastoma implanted in the Fischer rat brain

Three methods of drug administration (intra-venous, intra-

arterial and intra-arterial combined with blood brain barrierdisruption) were evaluated to determine which one optimizes

the tumor cell uptake, limits the toxicity and delivers the best

concomitance effect with radiotherapy. It was found that the

accumulation of drugs in tumor cells was significantly improved

when the intra-arterial route was used and further increased

after the transient opening of the blood brain barrier with

mannitol. The intra-arterial infusion of carboplatin or Lipoxal

in concomitance with radiation therapy leads to the best tumor

control as measured by an increase of mean survival time in

Fischer rats.

Charest G, Sanche L, Fortin D, Mathieu D, Paquette B. Optimization ofthe route of platinum drugs administration to optimize the concomitant

treatment with radiotherapy for glioblastoma implanted in the Fischer

rat brain. J Neurooncol. 2013 Sep 13. [Epub ahead of print] PMID:24026531

Efficient induction of differentiation and growth inhibition in

IDH1 mutant glioma cells by the DNMT Inhibitor Decitabine

Decitabine Structure

The drug decitabine was shown to reverse mutant IDH induced

hypermethylation and block in differentiation and promote

tumor control. This support the hypothesis that the extensive

DNA methylation helps maintain and "lock in" glioma cancer

cells in a dedifferentiated state. Thus, targeting the pathologic

DNA methylation in IDH mutant cells may have substantial im-

pact for exploring new treatment strategies for patients with

IDH mutant gliomas.

Turcan S, Fabius AW, Borodovsky A, Pedraza A, Brennan C, Huse J,Viale A, Riggins GJ, Chan TA. Efficient induction of differentiationand growth inhibition in IDH1 mutant glioma cells by the DNMTInhibitor Decitabine. Oncotarget. 2013 Sep 16. [Epub ahead of print]

PMID: 24077826

GLIOMA STEM CELL AS THERAPEUTIC TARGET

APO010, A Synthetic Hexameric CD95 Ligand, Induces Death

of Human Glioblastoma Stem-like Cells.

The synthetic hexameric cluster of differentiation 95 (CD95)

agonist APO010 was found to express antiproliferative effectsagainst a panel of previously well-defined glioma-initiating cells

(GIC) lines. Temozolomide enhanced sensitivity of GICs to

APO010.

Eisele G, Wolpert F, Decrey G, Weller M. APO010, A SyntheticHexameric CD95 Ligand, Induces Death of Human Glioblastoma Stem-

like Cells. Anticancer Res. 2013 Sep;33(9):3563-71.

TUMOR BIOLOGY

An EGFR wild type-EGFRvIII-HB-EGF feed-forward loop

regulates the activation of EGFRvIII

EGFRvIII is a key oncogene in glioblastoma (GBM). The authors

present a new model of EGFRvIII activation and propose that

oncogenic activation of EGFRvIII in glioma cells is driven by co-

expressed activated EGFR wild type (EGFRwt). They suggest

that an EGFRvIII-HB-EGF-EGFRwt feed-forward loop regulates

EGFRvIII activation. They demonstrate the existence of this loop

in human GBM that could be an attractive target for

therapeutic intervention.

Li L, Chakraborty S, Yang CR, Hatanpaa KJ, Cipher DJ,Puliyappadamba VT, Rehman A, Jiwani AJ, Mickey B, Madden C,

Raisanen J, Burma S, Saha D, Wang Z, Pingle SC, Kesari S, BoothmanDA, Habib AA. An EGFR wild type-EGFRvIII-HB-EGF feed-forwardloop regulates the act ivation of EGFRvIII. Oncogene. 2013 Sep 30. doi:10.1038/onc.2013.400. [Epub ahead of print] PMID: 24077285

Tumor progression and transformation of low-grade glial

tumors associated with pregnancy

The authors of this article documented the transformation from

low-grade gliomas to high-grade gliomas (WHO grade III and IV)

in young women during pregnancy. This has been previously

shown in meningiomas.

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Daras M, Cone C, Peters KB. Tumor progression and transformation of

low-grade glial tumors associated with pregnancy. J Neurooncol. 2013Sep 28. [Epub ahead of print]

PMID: 24078174

NATURAL PRODUCTS

Punicalagin induces apoptotic and autophagic cell death

Punicalagin Structure

In vitro treatment of human U87MG glioma cells with

punicalagin, a polyphenol isolated from pomegranates (Punica

granatum), induced cell death through both apoptotic and

autophagic pathways.

Wang SG, Huang MH, Li JH, Lai FI, Lee HM, Hsu YN. Punicalagininduces apoptotic and autophagic cell death in human U87MG glioma

cells. Acta Pharmacol Sin. 2013 Sep 30. doi: 10.1038/aps.2013.98.[Epub ahead of print] PMID: 24077634

FROM THE INDUSTRY

to-BBB Receives IND Approval for Novel Brain Cancer Drug,2B3-101

to-BBB, the brain drug delivery company based in Netherlands

is now ready to proceed to the Phase IIa part of a trial with its

internal lead product 2B3-101. Infotmation for patients canbe fond at:

http://www.tobbb.com/products/Patient_information

http://www.tobbb.com/content/nieuws/2013_08_19_to-bbb_receives_ind_approval_for_2b3-

101_and_proceeds_to_phase_iia_clinical_trials.pdf

BRAIN TUMOR

BIOLOGY & THERAPY

Meeting

12-13 June, 2014

Stockholm, Sweden

Submit your abstract

Early bird registration

11-30-2013

www.gliomas.org/nom

vol. 1 (7). october 2013

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