Page 322 - 2014 Printable Abstract Book
P. 322
mice and irradiate the tumor with 15 Gy single dose. We observed a significant tumor growth delay in HIF-
1α but not in HIF-2α myeloid-specific KO mice, suggesting that HIF-1 deficiency in myeloid cells can
sensitize tumors to irradiation. These results therefore suggest that HIF-1 in myeloid cells is a newest
target to be combined with radiotherapy.
(PS5-60) Enhanced Radiosensitization using Anti-Angiogenic Therapy in Sarcoma Tumors. Adriana
1
1
2
1
1
1
Haimovitz-Friedman ; Feng Wang ; Hongyan Li ; Nian-Hong Chen ; Rayon Glass ; Elisa De Stanchina ; and
3
Gary K. Schwartz , Department of Radiation Oncology, Memorial Sloan-Kettering Cancer Center, New
2
1
York, NY ; Assessment Core Facility, Memorial Sloan-Kettering Cancer Center, New York, NY ; and
3
Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY
Recent data in our laboratory indicates that engagement of host-derived microenvironmental
elements impact tumor response to single high dose radiation therapy (SDRT). In these studies we showed
that microvascular endothelial damage plays a critical role in tumor response as regulator of direct lethal
damage of SDRT. We used a genetic model of Acid Sphingomyelinase (ASMase)-deficient mice to prove
that activation of this enzyme by RT-induced damage in the endothelium is mandatory for tumor cure.
ASMase activation triggers ceramide-mediated apoptosis, and therein microvascular dysfunction, which
increased the vulnerability of tumor cells to lethal damage by radiation. In vitro, VEGF prevented RT-
induced ASMase activation and apoptosis in cultured endothelium, whilst anti-VEGF/VEGFR2 acts
conversely enhancing ASMase-mediated apoptosis. In vivo, anti-VEGF/VEGFR2 de-represses ASMase
activation only when delivered immediately prior to SDRT, thus synergistically increasing endothelial
apoptosis and tumor cure in a fibrosarcoma tumor model. Similar results were obtained using SDRT in
combination with Pazopanib (anti-VEGFR-1, VEGFR-2, VEGFR-3, PDGF-α/βand c-kit) in two animal models
of human sarcoma. A single dose of Pazopanib mimics the anti-VEGF/VEGFR impact on SDRT, increasing
ASMase activity in the serum and endothelial dysfunction, enhancing SDRT tumor cure, and exhibiting
critical dependence on timing relative to RT exposure, suggesting a mechanism of action identical to that
demonstrated for anti-VEGF/VEGFR2 antibodies. These results demonstrate the ability of Pazopanib to
shift the response towards tumor cure and could therefore have a significant impact on clinical trial
development.
(PS5-61) Relative biological effectiveness of the rat spinal cord after carbon ion irradiations with
1
1;2
1;2
different linear energy transfer. Maria Saager, Dipl.-Biol. ; Christin Glowa, PhD ; Peter Peschke, PhD ;
1
2
4
3
Stephan Brons, PhD ; Michael Scholz, PhD ; Peter Huber, MD, PhD ; Jürgen Debus, MD, PhD ; and Christian
1
1
Karger, PhD ; German Cancer Research Center, Heidelberg, Germany ; Dept. of Radiation Oncology,
2
University Hospital of Heidelberg, Heidelberg, Germany ; Heidelberg Ion Beam Therapy Center (HIT),
3
Heidelberg, Germany ; and Dept. of Biophysics, Helmholtz Center for Heavy Ion Research (GSI),
4
Darmstadt, Germany
Introduction: In carbon ion therapy, the relative biological effectiveness (RBE) is predicted by
mathematical models. Uncertainties in the predicted RBEs translate into uncertainty of the prescribed
dose, which can lead to severe side effects. Therefore, the RBE-models have to be validated using
experimental data. In the present study, the RBE for the rat spinal cord after carbon ion irradiation is
measured as a function of linear energy transfer (LET). Methods and Materials: As an extension of our
320 | P a g e
1α but not in HIF-2α myeloid-specific KO mice, suggesting that HIF-1 deficiency in myeloid cells can
sensitize tumors to irradiation. These results therefore suggest that HIF-1 in myeloid cells is a newest
target to be combined with radiotherapy.
(PS5-60) Enhanced Radiosensitization using Anti-Angiogenic Therapy in Sarcoma Tumors. Adriana
1
1
2
1
1
1
Haimovitz-Friedman ; Feng Wang ; Hongyan Li ; Nian-Hong Chen ; Rayon Glass ; Elisa De Stanchina ; and
3
Gary K. Schwartz , Department of Radiation Oncology, Memorial Sloan-Kettering Cancer Center, New
2
1
York, NY ; Assessment Core Facility, Memorial Sloan-Kettering Cancer Center, New York, NY ; and
3
Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY
Recent data in our laboratory indicates that engagement of host-derived microenvironmental
elements impact tumor response to single high dose radiation therapy (SDRT). In these studies we showed
that microvascular endothelial damage plays a critical role in tumor response as regulator of direct lethal
damage of SDRT. We used a genetic model of Acid Sphingomyelinase (ASMase)-deficient mice to prove
that activation of this enzyme by RT-induced damage in the endothelium is mandatory for tumor cure.
ASMase activation triggers ceramide-mediated apoptosis, and therein microvascular dysfunction, which
increased the vulnerability of tumor cells to lethal damage by radiation. In vitro, VEGF prevented RT-
induced ASMase activation and apoptosis in cultured endothelium, whilst anti-VEGF/VEGFR2 acts
conversely enhancing ASMase-mediated apoptosis. In vivo, anti-VEGF/VEGFR2 de-represses ASMase
activation only when delivered immediately prior to SDRT, thus synergistically increasing endothelial
apoptosis and tumor cure in a fibrosarcoma tumor model. Similar results were obtained using SDRT in
combination with Pazopanib (anti-VEGFR-1, VEGFR-2, VEGFR-3, PDGF-α/βand c-kit) in two animal models
of human sarcoma. A single dose of Pazopanib mimics the anti-VEGF/VEGFR impact on SDRT, increasing
ASMase activity in the serum and endothelial dysfunction, enhancing SDRT tumor cure, and exhibiting
critical dependence on timing relative to RT exposure, suggesting a mechanism of action identical to that
demonstrated for anti-VEGF/VEGFR2 antibodies. These results demonstrate the ability of Pazopanib to
shift the response towards tumor cure and could therefore have a significant impact on clinical trial
development.
(PS5-61) Relative biological effectiveness of the rat spinal cord after carbon ion irradiations with
1
1;2
1;2
different linear energy transfer. Maria Saager, Dipl.-Biol. ; Christin Glowa, PhD ; Peter Peschke, PhD ;
1
2
4
3
Stephan Brons, PhD ; Michael Scholz, PhD ; Peter Huber, MD, PhD ; Jürgen Debus, MD, PhD ; and Christian
1
1
Karger, PhD ; German Cancer Research Center, Heidelberg, Germany ; Dept. of Radiation Oncology,
2
University Hospital of Heidelberg, Heidelberg, Germany ; Heidelberg Ion Beam Therapy Center (HIT),
3
Heidelberg, Germany ; and Dept. of Biophysics, Helmholtz Center for Heavy Ion Research (GSI),
4
Darmstadt, Germany
Introduction: In carbon ion therapy, the relative biological effectiveness (RBE) is predicted by
mathematical models. Uncertainties in the predicted RBEs translate into uncertainty of the prescribed
dose, which can lead to severe side effects. Therefore, the RBE-models have to be validated using
experimental data. In the present study, the RBE for the rat spinal cord after carbon ion irradiation is
measured as a function of linear energy transfer (LET). Methods and Materials: As an extension of our
320 | P a g e
