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

126s Central Nervous System Tumors
2043 General Poster Session (Board #12F), Sat, 1:15 PM-5:15 PM
Expression of CXCR7, CXCR4, CXCR3 and their chemokine ligands in
glioblastoma. Presenting Author: Robert D. Berahovich, ChemoCentryx,
Inc., Mountain View, CA
Background: The chemokine receptors CXCR4 and CXCR7, and their shared
ligand CXCL12/SDF-1, have been implicated in multiple aspects of
tumorigenesis, including tumor cell proliferation, angiogenesis, vasculogenesis,
and metastasis. Recently, a role for CXCR4 and CXCR7 has been
postulated in the control of glioblastoma growth and vasculogenesis. We set
out to define the expression patterns of these proteins on primary
glioblastoma tumors and associated vasculature. Methods: First, a tumor
microarray containing grades 1, 3, and 4 glioma samples were analyzed by
immunohistochemical techniques for the expression of CXCR7. Second,
two glioblastoma microarrays were analyzed by the same technique for
CXCR7, CXCR4, and their shared chemokine ligand CXCL12. The same
microarrays were also probed for the expression of the additional CXCR7
ligand, CXCL11/ITAC, as well as the chemokine receptor CXCR3, which is
also a receptor for CXCL11. Tissues were scored in a blinded fashion by a
certified neuropathologist for both the intensity of signal and location of
signal for all proteins tested. Results: CXCR7 expression was largely
dependent on tumor grade, as the receptor was usually absent on most
grade 1 gliomas but was moderately-to-highly expressed in the majority of
anaplastic astrocytomas and glioblastomas. CXCR7 expression on tumorassociated
vasculature was seen in all samples and its expression level also
increased with glioma grade. In contrast to CXCR7, CXCR4 expression in
glioblastoma was usually limited to the glioma cells, with only infrequent
expression on the vasculature. Conversely, CXCL12 expression in glioblastoma
was usually limited to the vasculature. CXCR3 was detected in a
subset of glioblastomas, and only on the glioma cells. The CXCR7 and
CXCR3 ligand CXCL11 was, like CXCR7, expressed on both the glioma cells
and vasculature. Conclusions: These results, in light of prior evidence for
CXCR7 in tumor growth, suggest a positive role for CXCR7 in the
development of glioblastoma. Because CXCR7 colocalizes with its ligands,
CXCL12 and CXCL11, as well as their other receptors, CXCR4 and CXCR3,
the function of CXCR7 in glioblastoma may lie in the regulation of both the
CXCR4/CXCL12 and CXCR3/CXCL11 axes.
2045 General Poster Session (Board #12H), Sat, 1:15 PM-5:15 PM
A phase II multicentric study of sunitinib administered as upfront therapy
in glioblastoma: A study by the GEINO group. Presenting Author: Carmen
Balana, Institut Catala d’Oncologia Badalona, Barcelona, Spain
Background: Sunitinib is a multitargeted tyrosine kinase inhibitor that has
direct antitumor and antiangiogenesis activity through targeting VEGFR
1-2, PDGFR �-�, c-kit, bFGF, (CSF-1), FLT3 and RET. Experimental
studies in GB mice showed angiogenic activity, prolonged survival and
synergy with irradiation Methods: Eligible pts were �75 years with GB not
amenable to resection, PS�2, MMS �25. Treatment was sunitinib
37.5mg daily for 8 w before radiotherapy, during radiotherapy (60Gy, 6 w)
and after radiotherapy until disease progression. Primary endpoint was
overall response (OR) (RANO criteria) after 8wofsunitinib treatment
before radiotherapy. Secondary endpoints were % pts free of neurological
deterioration before radiotherapy, % pts who completed radiotherapy, PFS,
OS and 1-year survival. We used a Simon 2-stage design (12 ¡20) based
on OR to calculate the number of patients needed to detect at least 10% of
responses with � error of 0.05 and � error of 0.10. Twelve patients were
included in the first phase and one response was needed to continue study
accrual. Results: 12 pts were enrolled: 7 males, median age 65 years,
PS�1: 8pts, median MMS 26.5. Neurological deficit: 5pts, DXM treatment
10/12, non-EIDS 3/12. Treatment: 5 pts completed 8woftherapy, 2pts
completed 7 w, 4 pts � 6w. Toxicity G3 and 4: diarrhea (1pt), asthenia
(2pts), skin and EDDPP (2), mucositis (2), fatal CNS hemorrhage (1),
hypercholesterolemia and hypertriglycemia (1). OR was 1/12 SD, 11/12 P;
radiological response was SD in 5 pts but 4 pts progressed neurologically.
Only 2 pts completed radiotherapy plus sunitinib. The only SD received
treatment for 18 w. Median PFS was 7.5w (CI 95% 5.8-9.2), OS 16w (CI
95% 0.5-23.7), 1year OS: 0%. Conclusions: the trial was closed after the
first stage due to lack of response. Sunitinib is an inactive agent in
glioblastoma.
2044 General Poster Session (Board #12G), Sat, 1:15 PM-5:15 PM
Use of tumor-targeting salmonella typhimurium to eradicate human glioma
in an orthotopic model in nude mice. Presenting Author: Masashi Momiyama,
AntiCancer Inc., San Diego, CA
Background: Prognosis remains poor for glioma and therefore requires new
approaches. We have previously developed a genetically-engineered strain
of Salmonella typhimurium, A1-R, that targets tumors without overt toxicity
in mouse models (Proc. Natl. Acad. Sci. USA 102, 755-760, 2005; Cancer
Research 66, 7647-7652, 2006; Proc. Natl. Acad. Sci. USA 104,
10170-10174, 2007; Expert Opinion on Drug Discovery 7, 73-83, 2012).
In the present study, we demonstrated that Salmonella typhimurium A1-R
can inhibit and eradicate human glioma in an orthotopic nude mouse
model. Methods: S. typhimuirum A1-R was administered by injection
through a craniotomy open-window or intravenously in nude mice. To
establish the model, 2�105 U87 human glioma cells, expressing red
fluorescent protein (RFP), were injected stereotactically into the mouse
brain through the craniotomy open window. Two weeks after glioma-cell
implantation, mice were treated with S. typhimurium A1-R (2�107 CFU /
200 �l intravenous injection [i.v.] or 1�106 CFU / 1 �l intracranial
injection [i.c.]) once a week for 3 weeks. Results: Brain tumors were
observed by fluorescence imaging through the craniotomy open window
over time. S. typhimurium A1-R, administered i.c., inhibited brain tumor
growth 7.6-fold compared with untreated mice (p � 0.009) and improved
survival 73% (p � 0.001). Two of ten mice had their tumors eradicated.
Intravenous administration of S. typhimurium A1-R was not effective.
Conclusions: The results of the present study demonstrate that bacterial
therapy of glioma is a novel, effective and safe treatment strategy in a
highly treatment-resistance cancer in an orthothopic model, a first step
toward clinical development.
2046 General Poster Session (Board #13A), Sat, 1:15 PM-5:15 PM
Neuraxis imaging in leptomeningeal metastasis: A retrospective case
series. Presenting Author: Marc C. Chamberlain, Fred Hutchinson Cancer
Research Center, Seattle Cancer Care Alliance, Seattle, WA
Background: (and Objective) Leptomeningeal metastasis (LM) is a central
nervous system metastatic complication of cancer that affects the entire
neuraxis. Quantify imaging (brain and spine MRI and radio-isotope cerebrospinal
fluid [CSF] flow study) abnormalities in a retrospective case series of
patients with LM. Methods: 240 adult patients with LM (125 non-brain
solid tumor patients with positive CSF cytology; 40 non-brain solid tumor
patients with negative CSF cytology; 50 lymphoma and 40 leukemia
patients with positive CSF flow cytometry) underwent prior to treatment
brain and entire spine MRI and radio-isotope CSF flow studies (FS). Results:
Neuraxis MRI in pathologically defined patients was more often normal in
hematologic tumors (80-84%) compared to solid tumors (60%). Similarly,
FS was more often normal in hematologic tumors (90-92%) compared to
solid tumors (72-75%). However, neuraxis MRI and FS abnormalities (i.e.
CSF flow obstruction; nodular subarachnoid or parenchymal disease;
hydrocephalus) altered therapy by requiring CSF diversion, site specific
radiotherapy, systemic chemotherapy or recommending no further therapy
in one third of CSF cytology positive solid tumors and 15% of CSF flow
cytometry positive hematologic tumors. Conclusions: Notwithstanding less
frequent imaging abnormalities in hematologic tumors, similar to solid
tumors imaging abnormalities frequently result in treatment alteration for
patients with LM. Consequently, neuraxis imaging is recommended in both
tumor categories in patients being considered for LM-directed and in
particular intra-CSF chemotherapy treatment.
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