Principale Neuro-Oncology TMOD-16. BIOMATHEMATICAL MODEL OF PRONEURAL TUMORS SUGGESTS BEST CANDIDATES FOR PDGF-INHIBITOR...

TMOD-16. BIOMATHEMATICAL MODEL OF PRONEURAL TUMORS SUGGESTS BEST CANDIDATES FOR PDGF-INHIBITOR THERAPIES

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Volume:
18
Lingua:
english
Rivista:
Neuro-Oncology
DOI:
10.1093/neuonc/now212.886
Date:
November, 2016
File:
PDF, 41 KB
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Abstracts

expand the cells from one passage to the next was at least 3 weeks. Successful cell lines were harvested at different passages. Molecular characterization
of the tissue and cell lines were conducted using Sanger sequencing, Western
blot, immunocytochemistry, short tandem repeat analyses and methylation
arrays. RESULTS: 15 IDH1 mutant LGG cell lines were developed from 34
freshly collected specimens. IDH1 mutation exclusively reverted back to wild
type in all cell lines within several passages. Further molecular characterization of LGG associated genes (for example p53, ATRX, TERT) and epigenetic
studies through methylation arrays of paired tumor tissue samples and cell
lines enabled us to better determine the selective pressures associated with in
vitro culturing of patient derived glioma cell lines. CONCLUSION: We have
established and characterized LGG cell lines derived from patient tumor material and provided a unique resource to better understand LGG biology and
improve targeted treatment strategies whilst also detailing the extent to which
in vitro models of patient derived glioma cell lines mimic their tumor of origin.
TMOD-15. MLN8237 TREATMENT IN AN ORTHOXENOGRAFT
RODENT MODEL FOR MALIGNANT PERIPHERAL NERVE SHEATH
TUMORS
Oliver Mrowczynski, Russell Payne, Achuthamangalam Madhankumar,
Becky Webb, Elias Rizk, Kimberly Harbaugh and James Connor; Penn State
Hershey, Hershey, PA, USA

TMOD-16. BIOMATHEMATICAL MODEL OF PRONEURAL
TUMORS SUGGESTS BEST CANDIDATES FOR PDGF-INHIBITOR
THERAPIES
Susan Massey1, Peter Canoll2 and Kristin Swanson1; 1Precision
Neurotherapeutics (PNT) Innovation Lab, Mayo Clinic, Phoenix, AZ, USA,
2Dept. of Pathology and Cell Biology, Columbia University Medical Center,
New York, NY, USA
Platelet Derived Growth Factor (PDGF) is often over-expressed in gliomas, where it can drive tumor growth via autocrine stimulation of PDGF
receptor (PDGFR) expressing glioma cells and via paracrine stimulation of
non-neoplastic oligodendrocyte progenitor cells (OPCs), which also express
P; DGFRa. To date, the use of PDGF inhibitors has remained largely unsuccessful at improving patient outcomes in glioblastoma; however, this may be
due to inadequate targeting of these agents to the best candidates. In particular, these therapies have been given in the recurrent setting, when tumors
that had been predominantly comprised by OPCs and OPC-like glioma
cells (e.g., proneural subtype) have transformed to a mesenchymal phenotype with fewer OPC-like cells, thereby precluding the opportunity to target
OPC-like cells with these agents. Using a mathematical model of PDGFdriven glioma, we explore which patients might receive the greatest benefit
from PDGF-targeted therapies. The results of our mathematical model show
that tumors with higher levels PDGF signaling recruit more OPCs and grow
faster, resulting in larger but less infiltrating tumors. By incorporating different treatment simulations in our model, we show that PDGF inhibition
results in decreased OPC recruitment, which leads to slower growing, but
more diffusely infiltrating tumors. This suggests that PDGF inhibitors may
be most effective at treating patients with more rapidly proliferating, less
infiltrative tumors which show a predominance of OPCs on immunohisto-

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NEURO-ONCOLOGY

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NO VE M BE R 201 6

TMOD-17. CONVERGENCE OF BMI1 AND CHD7 ON ERK
SIGNALLING IN MEDULLOBLASTOMA
Silvia Marino1, Adrian Dubuc2, Mariane Da Cunha Jaeger1, Sorana Morrissy2,
Michael Taylor2 and Xinyu Zhang1; 1Blizard Institute, Barts Medical School,
Queen Mary University of London, London, United Kingdom, 2Department
of Laboratory Medicine and Pathobiology, University of Toronto, Toronto,
Canada
Medulloblastoma is the most common malignant brain tumour of childhood, and a common cause of pediatric morbidity and mortality. Medulloblastomas have been dissected into four distinct molecular subgroups (WNT,
SHH, Group 3, Group 4) with divergent clinical and biological profiles. The
Polycomb group protein Bmi1 is upregulated in a variety of cancers, has a
positive correlation with clinical grade/stage and poor prognosis and it is a
highly druggable molecule. Bmi1 is overexpressed across all MB subgroups;
the growth of SHH and Group 4 MB is dependent on Bmi1 expression.
Genome wide in vivo insertional mutagenesis (T2Onc2) driven by the Sleeping Beauty (SB11) transposase in glutamatergic progenitor cells engineered
to over-express Bmi1 results in medulloblastoma formation, while neither
Bmi1 over-expression nor T2Onc2 transposition alone drives tumorigenesis.
On the Bmi1 over-expressing background, we observe frequent T2Onc2
inactivating insertions in the chromatin remodelling factor Chd7 (Chromodomain helicase DNA binding factor 7), suggesting that Bmi1 overexpression and Chd7 loss of function cooperate to induce medulloblastoma.
High expression of BMI1 in combination with low expression of CHD7 is
associated with a poor prognosis in human medulloblastoma. Loss of function mutations of CHD7are observed in medulloblastoma, particularly in
Group 4. CHD7 knockdown in patient-derived Group 4 medulloblastoma
cells led to increased proliferation and increased expression of markers of
undifferentiated and highly proliferative progenitor cells both in vitro and
in xenografts. Importantly, we show the BMI1-dependency of the phenotype
observed upon CHD7 knockdown and the molecular convergence on ERK
signalling. These finding extend the current knowledge of the role of BMI1
and CHD7 in medulloblastoma pathogenesis and raise the possibility that
pharmacological targeting of BMI1 or ERK may be particularly indicated in
a subgroup of medulloblastoma with low expression level of CHD7.
TMOD-18. THREE-DIMENSIONAL MICROTUMORS IN
PHYSIOLOGIC MICROENVIRONMENTS MAINTAIN BRAIN
TUMOR INITIATING CELLS
Ashley Gilbert1, Kiera Walker2, Anh Tran2, Yancey Gillespie2, Raj Singh1
and Anita Hjelmeland2; 1Vivo Biosciences Inc., Birmingham, AL, USA,
2University of Alabama at Birmingham, Birmingham, AL, USA
Elucidation of mechanisms of brain tumor initiating cell (BTIC) maintenance and therapeutic resistance offers great promise for development of
novel anti-tumor treatments. Current leading studies rely on BTIC isolation
from patient-derived xenografts followed by propagation as neurospheres.
As this process is expensive and time-consuming, we determined if threedimensional microtumors were an alternative in vitro method for modeling
tumor growth via BITC maintenance and/or enrichment. Brain tumor cells
were grown as neurospheres or as microtumors produced using a humanderived biomatrix HuBiogelTM and maintained with physiologically relevant
microenvironments. Percentages of BITCs were then determined based on
cell surface marker expression (CD133), label retention (carboxyfluorescein succinimidyl ester; CFSE), and tumorsphere formation capacity. Our
data demonstrate that expansion of brain tumor cells as hypoxic and nutrient restricted microtumors significantly increased the percentage of both
CD133+ and CFSE+ cells. For example, fifteen percent of all brain tumor
cells from a xenograft propagated as microtumors were CD133+, whereas
only one percent of neurosphere cultured cells expressed the BTIC marker.
Relative to CD133, CFSE was retained in a higher percentage of cells, but
CFSE+ cells were still increased in the microtumor condition in comparison
to neurospheres. We further demonstrate that BTIC-marker positive cells
isolated from microtumors maintain neurosphere formation capacity in the
in vitro limiting dilution assay and tumorigenic potential in vivo. These data
demonstrate that microtumors can be a useful three-dimensional biological
model for the study of BTIC maintenance and targeting.
TMOD-19. PROPERTIES OF COGNITIVE DEVELOPMENT OF
CHILDREN WITH CEREBELLAR TUMOR
Varvara Chizhova, Anastasia Shcheglova, Julia Burdukova and
Olga Alekseeva; Moscow State University of Psychology and Education,
Moscow, Russian Federation
The aim of the study was to estimate the influence of brain tumor and
tumor’s localization on children’s cognitive development. Two groups of

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Malignant peripheral nerve sheath tumors (MPNSTs) are soft tissue sarcomas that arise from peripheral nerves and often occur in the extremities.
MPNSTs arise sporadically or in the neurofibromatosis type one (NF1). NF1
is an autosomal-dominant disorder characterized by neurofibromas, cutaneous hyperpigmentation, and intellectual deficits affecting 1 in 3000 births.
The lifetime risk of a person with NF1 developing MPNSTs ranges between
8-13%. MPNSTs have increased expression of the oncogene Aurora kinase
A. This leads to enhanced cell proliferation, making MPNSTs extremely
aggressive, with high potential for metastasis, and devastating prognosis, with
five year survival estimates ranging from a dismal 15-60%. MPNSTs are currently treated with surgical resection, sometimes requiring limb amputation,
as well as chemoradiation, all of which demonstrate limited effectiveness, and
highlight the necessity for novel therapies. To evaluate the effectiveness of new
treatments, a translationally accurate, robust, and cost-effective model is crucial. A major goal of this study was to produce an orthotopic xenograft murine
MPNST model for evaluation of novel therapies, which we created by intraneural injection of luciferase transfected MPNST cells into the mice sciatic
nerve. Our model circumvents drawbacks of previous in vivo models by producing a robust tumor in the physiologically relevant microenvironment of the
nerve that allows for accurate tumor burden quantification through luciferin
fluorescence. Another goal of this study was to demonstrate the effectiveness of
MLN8237 for MPNST treatment. MLN8237 is an aurora kinase A inhibitor
that we demonstrate to decrease MPNST burden by 54%. This study provides
a robust and reproducible MPNST model, allowing for the advancement of
MPNST therapy. This study also demonstrates the effectiveness of MLN8237
for MPNST treatment. Together, our data has major implications on the future
of MPNST research by providing a robust murine model as well providing
evidence that MLN8237 is an effective treatment for MPNSTs.

chemistry. Further, the model suggests that they should be given earlier in the
disease course, i.e., prior to recurrence, but following resection.