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

118s Central Nervous System Tumors
2011 Clinical Science Symposium, Sat, 1:15 PM-2:45 PM
Modulation of antiangiogenic resistance: Targeting the JAK/STAT3 pathway
in glioblastoma. Presenting Author: John Frederick De Groot, University
of Texas M. D. Anderson Cancer Center, Houston, TX
Background: Determining the mechanism of treatment failure of antiangiogenic
therapies would provide insight into either potential combination
approaches or salvage therapies. Methods: Tumor and monocyte expression
of phosphorylated-signal transducer and activator of transcription 3 (p-
STAT3) was compared between recurrent glioblastoma patients treated
with either conventional chemotherapy or bevacizumab (BEV), and secondarily
validated in murine model systems of intracerebral glioma treated with
either BEV or cediranib. The JAK/STAT3 inhibitor AZD1480 alone and in
combination with cediranib was evaluated in immunocompetent mice
bearing intracerebral GL261 xenografts to evaluate therapeutic synergy.
Results: Human glioblastoma patients failing BEV have an increase in
intratumoral p-STAT3- expression with a mean number of p-STAT3
expressing cells of 36.5 � 8.6% (n�7) compared to a mean of 20.2 � 4%
(n�5) in patients never receiving antiangiogenic therapy. In a separate
cohort of recurrent glioblastoma patients, the up-regulation of p-STAT3
was detected in monocytes within 24 hours after initial BEV administration.
In intracranial xenograft models, both BEV and cediranib extended
median animal survival time, but during treatment failure BEV increased
the mean percentage of p-STAT3-expressing cells to 24.6 � 6.4%
(P�0.0011), and cediranib increased this to 16.2 � 1.8% (P�0.0125)
relative to 9.0 � 4.4% in controls. Administration of the JAK/STAT3
inhibitor AZD1480 alone and in combination with cediranib reduced tumor
hypoxia and infiltration of VEGF inhibitor-induced p-STAT3 macrophages.
The combination reduced tumor volume by 80% compared to untreated
controls, and by 65% compared to cediranib or AZD1480 treatment alone.
Microvascular density and tumor de-differentiation were reduced, indicating
that up-regulation of the STAT3 pathway can mediate resistance to
antiangiogenic therapy. Conclusions: Cumulatively, these data suggest that
a prominent mechanism of failure of anti-VEGF therapy in malignant
glioma patients involves up-regulation of the STAT3 pathway, and resistance
to antiangiogenic therapy can be modulated with inhibitors of the
JAK/STAT pathway.
2013 Poster Discussion Session (Board #1), Fri, 1:00 PM-5:00 PM and
4:30 PM-5:30 PM
Phase I safety and pharmacokinetic (PK) study of veliparib in combination
with whole brain radiation therapy (WBRT) in patients (pts) with brain
metastases. Presenting Author: Minesh P. Mehta, Northwestern University,
Chicago, IL
Background: Veliparib is an oral PARP-1 and -2 inhibitor that enhances the
antitumor activity of DNA damaging agents including radiation therapy in
vivo. In pre-clinical models, veliparib crosses the blood-brain barrier. This
ongoing phase I dose-escalation study evaluates the safety, PK, and
provides preliminary antitumor activity of veliparib in combination with
WBRT in pts with brain metastases. Methods: Pts with brain metastases
from non-CNS primary solid malignancy, adequate organ function, RPA
Class 2, and KPS �70 were treated with WBRT (37.5 Gy in 15 fractions or
30 Gy in 10 fractions) QD with veliparib BID with every fraction of WBRT in
escalating doses of 10, 20, 30, 50, 100, 150, and 200 mg; the final WBRT
fraction was followed by 1 extra day of veliparib. Safety, PK, and tumor
response by RECIST were assessed. Results: At the time of reporting 59 pts
(M/F, 21/38; median age 57 y) had been treated. Baseline KPS was 70,
80, 90, and 100 in 6.8, 32.2, 40.7, and 20.3% pts, respectively; primary
tumor types were breast (n�20), NSCLC (n�20), melanoma (n�9),
colorectal (n�2), and others (n�8); 71.2% pts had multiple lesions; and
18.6% had prior brain SRS. Grade 3/4 treatment-emergent adverse events
(TEAEs; �5%) were fatigue (6.8%), anemia (5.1%), hyponatraemia
(5.1%), and thrombocytopenia (5.1%); other TEAEs (�20%) were fatigue
(57.6%), headache (42.4%), nausea (40.7%), alopecia (28.8%), vomiting
(22%), radiation skin reactions (22%), and decreased appetite (22%). PK
of veliparib were approximately dose-proportional, with oral clearance of
21.6 � 14.2 L/h (mean � SD, n�45), minimal drug accumulation at day
15, and no significant effect of food on bioavailability. Tumor response was
evaluable in 48 pts. Best tumor response and median survival were 37.5%
and 10 months (m) for NSCLC, and 52.9% and 12.5 m for breast cancer
(excluding pts with leptomeningeal disease). Conclusions: Addition of
veliparib up to 200 mg BID was well tolerated with concurrent WBRT and
dose escalation ongoing. The PK of veliparib was dose proportional with no
food effect. Preliminary antitumor activity is encouraging and informative
for the design of more definitive trials.
2012 Clinical Science Symposium, Sat, 1:15 PM-2:45 PM
Effects of cediranib (VEGF signaling inhibitor) on edema in newly diagnosed
glioblastoma patients during initial chemoradiation. Presenting
Author: Pavlina Polaskova, Martinos Center for Biomedical Imaging,
Massachusetts General Hospital, Charlestown, MA
Background: A significant benefit of antiangiogenic therapy is control of
brain edema. We evaluated the impact of adding cediranib to standard
chemoradiation (CRT) on peritumoral edema in patients with newly
diagnosed glioblastoma(GBM) during the initial 6 weeks of CRT. Methods:
Two cohorts of patients were enrolled in two clinical trials. The control
group (N�13) received radiation for 6 weeks plus temozolomide. The
cediranib (CED) group received standard CRT plus daily cediranib (N�34).
MRIs were performed at baseline and weekly during CRT. Volumes of
interest (VOIs) were drawn outlining the enhancing tumor on T1-weighted
post contrast images and the abnormal FLAIR hyperintensity. ADC (apparent
diffusion coefficient) maps were calculated from diffusion-weighted
images and histograms of the distribution of ADC values created for each
visit using the baseline FLAIR VOI to characterize the peritumoraledema.
Patients were on stable or decreasing doses of steroids. Results: In the CED
group, T1 and FLAIR VOI decreased during CRT vs controls where T1 VOI
did not change and FLAIR VOI increased. By the end of CRT, the mode of
the ADC histogram in the CED group shifted to the left while the mode of
the controls shifted to the right. The skewness, a measure of asymmetry of
the distribution, increased in the CED group and decreased in controls.
Conclusions: In patients with newly diagnosed GBM treated with CRT and
cediranib, tumor volume decreased on T1 and FLAIR images whereas the
FLAIR volume significantly increased in the control group suggesting
increased edema. The shift of mode to the right and decreasing skewness in
controls (indicating an increase in the proportion of very high ADC values)
suggests that adding cediranibprevented the development of edema and
contributed to the resolution of existing edema. Preventing the edema by
adding anti-VEGF treatment may improve the tolerability of CRT for GBM
patients.
T1 VOI
(ml)
FLAIR VOI
(ml)
ADC histogram mode
(x10 -4 �m 2 /ms)
ADC histogram
skewness
Baseline 6 wks Baseline 6 wks Baseline 6 wks Baseline 6 wks
CED 18.0 11.5 36.0 32.9 10.8 10.1 2.64 2.97
Control 14.8 14.5 25.9 57.1* 9.5 11.8* 2.62 2.42
* Significant difference between CED and controls (p � .05).
2014 Poster Discussion Session (Board #2), Fri, 1:00 PM-5:00 PM and
4:30 PM-5:30 PM
FIP200 and Rb1 expression in CNS metastasis from breast cancer (CNS
met): Potential predictors of patient outcome. Presenting Author: Nooshin
Hashemi Sadraei, Cleveland Clinic Foundation, Cleveland, OH
Background: Patients with CNS met have a poor outcome with significant
variation in overall survival. No marker to predict survival exists. Rb1 is a
negative regulator of the cell cycle, and FiP200 is an upstream signaling
node that is distributed between the nucleus and cytoplasm. Nuclear
FIP200 inhibits cell proliferation by promoting expression of Rb1, whereas
cytoplasmic FIP200 promotes cell survival through autophagy. Previously
FIP200 deletion/mutation has been reported in 20% of primary invasive
breast cancer [BR ca] patients. FIP200 cellular localization and genetic
alterations have not been examined in CNS met. Methods: A retrospective
analysis of BR ca and CNS met was performed based on tissue availability
from 2 institutions. FIP200 and Rb1 expression and localization was
evaluated by immunohistochemistry. Genetic alterations were evaluated by
DNA array analysis. Results: 80 patients (42 BR ca and 38 CNS met) were
identified. Overall CNS met samples had significantly higher levels of
cytoplasmic FIP200 as compared to BR ca (52% vs 24% respectively,
p�0.0002) and increased expression of FIP200 around areas of hypoxia/
necrosis, consistent with increased autophagy. There was also a significant
increase in expression of nuclear FIP200 and Rb1 in the CNS met
compared to BR ca (p�0.0007 and p�0.0055 respectively). Median
survival from development of CNS met was longer in the group with high
levels of nuclear Rb1; 14 (3-27) vs 20 (12-33) months (low expression �
20% vs high � 20%, p�0.1). The same finding was observed with FIP200,
longer survival was observed with high nuclear expression; 16 (7-33) vs 19
(0.4-27) months (low expression �20% vs high � 20%, p�0.2). Our DNA
analysis for copy number variation and LOH in CNS met revealed no
deletion in Rb1 or FIP200. Conclusions: The pattern of expression of Rb1
and FIP200 in CNS met is different from BR ca. Notably, cytoplasmic
FIP200 which promotes cell survival is highly expressed in CNS mets vs BR
ca. This suggests metastatic breast cancer cells utilize autophagy as a
survival mechanism. In addition, there is a trend to better survival of those
patients with CNS met who express high nuclear FIP200 and Rb1, both of
which have anti-proliferative roles in the nucleus.
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