Annual Meeting Proceedings Part 1 - American Society of Clinical ...

2055 General Poster Session (Board #14B), Sat, 1:15 PM-5:15 PM
Effect of the integrin inhibitor cilengitide on TGF-beta signaling. Presenting
Author: Michael Weller, University Hospital Zurich, Zurich, Switzerland
Background: Glioblastoma is the most malignant form of intrinsic brain
tumors. One of its characteristic features, angiogenesis, is mediated by the
expression of integrins �v�3 and �v�5 on tumor-associated vasculature.
Cilengitide is a synthetic peptide which inhibits ligand binding to the �v�3
and �v�5 integrins. The addition of cilengitide to the standard treatment
regimen of radiochemotherapy in patients with newly diagnosed glioblastoma
demonstrated promising results without significant toxicity which led
to the initiation of a randomized phase registration III trial. Besides other
functions, av-integrins can be involved in the activation of the cytokine
transforming growth factor (TGF)-� which contributes to the malignant
phenotype of glioma cells. Methods: Integrin expression was examined by
immunohistochemistry and flow cytometry. The effects of cilengitide on
TGF-� signaling in glioma cells were investigated by PCR, immunoblot and
ELISA. Further assessments included reporter assays and glioma xenografts
in nude mice. Results: The target integrins of cilengitide are
expressed in glioblastoma blood vessels and tumor cells. Exposure to
cilengitide results in detachment and reduced phosphorylation of Smad2
in most glioma cell lines, including stem-like glioma cells. Furthermore,
exposure of glioma cells to cilengitide is associated with reduced TGF-�mediated
reporter gene activity. Smad2 phosphorylation, but not attachment,
can be rescued by co-exposure to recombinant TGF-�. Cilengitide
results in decreased TGF-�1 and TGF-�2 mRNA and protein expression and
loss of transcriptional activity of the TGF-� promoter. Blocking antibodies
to integrins �v, �v�3 or�v�5, or silencing of integrins �v, �3, �5 or�8 by
RNA interference mimics the effects of cilengitide on TGF-� expression.
Intracranial LN-308 glioma xenografts in nude mice display reduced
pSmad2 levels in response to cilengitide. Conclusions: This study demonstrate
a novel mechanism which may in part mediate anti-glioblastoma
activity of cilengitide. These anti-TGF-� properties of cilengitide might be
exploited in future clinical trials.
2057 General Poster Session (Board #14D), Sat, 1:15 PM-5:15 PM
Natural history of glioblastoma in the modern era: Longitudinal results from
a large prospective Italian register. Presenting Author: Alba Ariela Brandes,
Medical Oncology Department, Bellaria-Maggiore Hospital, Azienda USL of
Bologna, Bologna, Italy
Background: The role of temozolomide (TMZ) concurrent with and adjuvant
to radiotherapy (RT) in the treatment of glioblastoma (GBM) has been
demonstrated by the EORTC 22981/26981-NCIC CE.3 (EORTC/NCIC)
randomized trial, and has been widely accepted as the standard treatment.
The impact of RT/TMZ in the general patient population was assessed in
the context of the Registry of the Project of Emilia-Romagna Region in
Neuro-Oncology (PERNO), that represents the first italian prospectic
observational population-based study in neuro-oncology. Methods: Approvals
from local Ethical Committees were obtained by 8 participating centres.
Patients (pts) who met the following inclusion criteria were evaluated: age
�18 years; PS 0-3; histologically confirmed GBM, no previous or concomitant
non glial tumoral disease, resident in Emilia Romagna region. The data
were prospectively collected. Results: From January 2009 to January 2011,
194 GBM pts were enrolled. The median age was 62.5, with 26% of pts
over 70 years. After surgery pts received RT/TMZ (73%), RT alone (19%),
TMZ alone (5%) or no further treatment (3%); 22% were included in
clinical trials. Median overall survival (OS) was 12.9 months. Pts �70
years received RT/TMZ in 85% of cases. In this group of pts mOS was 17
months (95%CI: 15.4–18.6). Interestingly, pts �70 years included in
experimental clinical trials showed a significant OS improvement (p�0.04).
In multivariate analysis, only extent of surgery (p�0.047), KPS (p�0.01)
and RT/TMZ (p�0.001) were associated with OS in pts �70 years.
Conclusions: Our population data reproduces the beneficial effect of
RT/TMZ from the EORTC/NCIC randomized trial, confirming how this
successful approach as been widely incorporated in daily practice. Interestingly,
our data suggest that the survival of GBM pts treated with RT/TMZ
could be greater than patients treated with RT/TMZ in the EORTC/NCIC
trial at the beginning of this century.
Central Nervous System Tumors
129s
2056 General Poster Session (Board #14C), Sat, 1:15 PM-5:15 PM
Impaired expression of ketone metabolizing enzymes in malignant gliomas:
Implication for ketogenic diet therapy. Presenting Author: Howard T.
Chang, Michigan State University, East Lansing, MI
Background: Malignant glial cells may have altered expression of mitochondrial
enzymes that are key for deriving energy from ketones. The novel
strategy of treating malignant gliomas with a ketogenic diet has been tested
in animal models with promising results. To evaluate the applicability of
these findings to human patients we tested the hypothesis that high grade
human gliomas may lack or have decreased expression of mitochondrial
enzymes that are important for metabolizing ketones. Methods: We evaluated
the expression of 2 key mitochondrial enzymes involved in ketone
metabolism in 22 patients (17 males and 5 females, mean age 55,range
30-85) with either glioblastoma (GBM, WHO grade IV) or anaplastic glioma
(WHO grade III) (Table). Immunohistochemistry reactions were performed
on formalin-fixed paraffin-embedded sections from brain biopsies, using
antibodies raised against succinyl CoA: 3-oxoacid CoA transferase (OXCT1)
and 3-hydroxybutyrate dehydrogenase 1 (BDH1). Immunoreactivities were
graded using a semi-quantitative scale based on the percentage of positive
cells: negative (NEG) � 5%; intermediate (INT) 5-20%; and positive (POS)
more than 20%. Focal non-neoplastic “normal” brain tissue present within
the specimens expressed both enzymes and served as an internal positive
control. Results: Either absent or marked decreased expression of OXCT1
and BDH1 were observed in most GBM and anaplastic glioma. Concordance
for absent or marked decrease expression of both OXCT1 and BDH1
was observed in 14 of the 17 (82%) GBM’s, and 1 of 5 (20%) anaplastic
gliomas. Conclusions: These data support the rationale for a pilot clinical
study investigating the therapeutic utility of a ketogenic diet in selected
glioma patients. Malignant gliomas with diminished expression of key
enzymes (e.g., OXCT1, BDH1) may benefit from the ketogenic diet therapy,
whereas those with positive expression of these enzymes likely will not.
OXCT1 BDH1
N NEG INT POS NEG INT POS
GBM 17 10 4 3 11 6 0
Anaplastic glioma 5 0 1 4 1 3 1
2058 General Poster Session (Board #14E), Sat, 1:15 PM-5:15 PM
Quality of life in patients with malignant brain tumors. Presenting Author:
Ali Choucair, Norton Neuroscience Institute, Louisville, KY
Background: A positive quality of life (QOL) serves as an important outcome
priority in patients with malignant brain tumors whose survival is limited by
tumor resistance to treatment. The FDA and ASCO have designated QOL as
an outcome secondary in importance to survival. We conducted a prospective
longitudinal collection of QOL measures (EORTC QLQ-C30, EORTC
QLQ-BN20, and Hospital Anxiety and Depression Scale [HADS]) coupled
with clinical standards of care (brain MRI and clinical history and physical
examinations) in patients with newly diagnosed primary brain tumors
(PBT). We also examined the QOL measures over time as related to tumor
progression. Methods: Under an IRB-approved protocol, we reviewed the
validated QOL measures and standard clinical measures from patients who
were newly diagnosed with PBT. The patients were followed every 3 months
over 2 years. No proxies were allowed. A total of 52 patients were enrolled
in the study. Survey responses were compared between two tumor groups of
patients: patients with tumor recurrence and/or died and patients without a
recurrence (n�26 each group). A total of 17 patients succumbed to a
tumor-related death. Statistical analysis utilizing non-parametric t-tests
and Wilcoxon sign tests assessed QOL responses. Results: Significant group
differences were noted in the questions of the QOL measures surveys with
more negative responses in the recurrence group. The questions with
significant group differences on the EORTC QLQ-C30 ranged from symptoms
of dyspnea (p�.05) and difficulty sleeping (p�.05) as well as a poor
QOL (p�.005) and pain interfering with daily activities (p�.05). Significant
group differences of questions on the EORTC QLQ-BN20 included
weakness of the legs (p�.05), coordination difficulties (p�.005), and
unsteady gait (p�.05). Significant group differences of questions on the
HADS reflected a patient who is �slowed down� (p�.01) and �frightened�
(p�.05). Conclusions: Our analysis of questions answered by patients with
newly diagnosed PBT may shed light on the impact of cancer and its
treatment and potential recurrence on a patient’s QOL. Further research is
warranted to incorporate QOL measurements into improvement of patient
care and their use in clinical trials and as a prognostic indicator.
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