Page 170 - 2014 Printable Abstract Book
P. 170
(PS2-60) Modeling radiation-induced vascular effects of high-dose versus standard-dose radiation in an
1
orthotopic mouse model of high-risk neuroblastoma. Fauzia Shaikh, B.A. ; Angela Kadenhe-Chiweshe,
2
2
2
3
1
MD ; K. S.Clifford. Chao ; Sonia Hernandez, PhD ; Lynn Forrester, B.A. ; Darrell Yamashiro, MD PhD ; Tom
1
4
K. Hei ; and Eileen P. Connolly, MD PhD, Columbia University Medical Center- Department of Radiation
1
Oncology, New York, NY ; Columbia University Medical Center- Pediatric Tumor Biology Lab, New York,
2
3
NY ; University of Chicago, Chicago, IL ; and Columbia University Medical Center- Center for Radiological
Research, New York, NY
4
Radiation therapy (RT) is integral to the treatment of high-risk neuroblastoma (NB). However, its
efficacy is limited by normal tissue toxicity. This has led to a search for RT-enhancing strategies such as
high-dose intraoperative RT. Given that large single fraction doses of RT are known to disrupt tumor
vasculature, this ablative effect may be amplified in neuroblastoma, a highly vascular tumor. We seek to
characterize the vascular effects of high dose RT in this preclinical model. Methods: The MYCN-amplified
human cell line NGP-Luc was implanted intrarenally in athymic mice (n=10). After 3-5 weeks, mice with
established tumors were selected, imaged and randomized to receive either a single fraction of 2Gy (n=4),
12Gy (n=4) or no RT (n=2). Mice were sacrificed 24 hours after RT; tumors were processed and
histopathologically analyzed. Results: Tumors treated with 2 and 12Gy were matched for size prior to RT,
with no difference in tumor volume (p>0.05). Upon sacrifice, those treated to 12Gy had increased tumor
weight compared to the 2Gy group (p=0.036). Analysis of tumors by hematoxylin and eosin (H&E) staining
revealed greater hemorrhage and red blood cell (RBC) extravasation in the 12Gy group compared to the
2Gy group and control mice. However, immunohistochemistry (IHC) for collagen IV and endomucin did
not reveal any significant disruption of the endothelium. Analysis of apoptosis by TUNEL stain revealed
intermittent regions of markedly increased apoptosis in the 12Gy samples, yet there was no difference in
density of apoptosis in the tumor tissue between these regions and the other two groups. Neither high
nor low-dose RT had any effect on circulating tumor cells measured by blood luciferase activity.
Conclusions: Analysis of mouse tumors 24 hours after irradiation with high dose RT demonstrates early
differences in comparison to tumors treated with low dose RT and no RT, such as increased hemorrhage,
RBC extravasation and necrosis. These findings suggest functional disruption of tumor vasculature,
without any clear breakdown of the correlating endothelium on IHC. We believe the regions of early
apoptotic activity likely correlate to regions affected by functional disruption of the vasculature. Further
analysis with in-vivo imaging of tumor vasculature with contrast-enhanced ultrasound is ongoing.
(PS2-61) HIF-1α responds to radiation by activating unique targets to promote radiation resistance via
a tumor-cell autonomous mechanism. Minsi Zhang; Qiong Qiu; Hooney Min; Zhizhong Li; Diana Cardona;
Yan Ma; Amanda Nichols; Tracy Han; Lixia Luo; Thies Schroeder; Mark W. Dewhirst; Christopher B.
Newgard; Jeffrey C. Rathmell; and David G. Kirsch, Duke University, Durham, NC
Hypoxia is a major cause of radiation resistance, which leads to local recurrence after radiation
therapy (RT). While hypoxia can promote tumor cell survival post-RT because there is less oxygen to
generate DNA adducts which are hard to repair, whether signaling pathways triggered by hypoxia
contribute to radiation resistance is poorly understood. For example, intratumoral hypoxia can increase
hypoxia-inducible factor-1α (HIF-1α), which may regulate pathways that contribute to radiation
sensitization and radiation resistance. To clarify the role of HIF-1α in regulating tumor response to
radiation therapy, we deleted HIF-1α in a novel primary mouse model of STS with conditional activation
168 | P a g e
1
orthotopic mouse model of high-risk neuroblastoma. Fauzia Shaikh, B.A. ; Angela Kadenhe-Chiweshe,
2
2
2
3
1
MD ; K. S.Clifford. Chao ; Sonia Hernandez, PhD ; Lynn Forrester, B.A. ; Darrell Yamashiro, MD PhD ; Tom
1
4
K. Hei ; and Eileen P. Connolly, MD PhD, Columbia University Medical Center- Department of Radiation
1
Oncology, New York, NY ; Columbia University Medical Center- Pediatric Tumor Biology Lab, New York,
2
3
NY ; University of Chicago, Chicago, IL ; and Columbia University Medical Center- Center for Radiological
Research, New York, NY
4
Radiation therapy (RT) is integral to the treatment of high-risk neuroblastoma (NB). However, its
efficacy is limited by normal tissue toxicity. This has led to a search for RT-enhancing strategies such as
high-dose intraoperative RT. Given that large single fraction doses of RT are known to disrupt tumor
vasculature, this ablative effect may be amplified in neuroblastoma, a highly vascular tumor. We seek to
characterize the vascular effects of high dose RT in this preclinical model. Methods: The MYCN-amplified
human cell line NGP-Luc was implanted intrarenally in athymic mice (n=10). After 3-5 weeks, mice with
established tumors were selected, imaged and randomized to receive either a single fraction of 2Gy (n=4),
12Gy (n=4) or no RT (n=2). Mice were sacrificed 24 hours after RT; tumors were processed and
histopathologically analyzed. Results: Tumors treated with 2 and 12Gy were matched for size prior to RT,
with no difference in tumor volume (p>0.05). Upon sacrifice, those treated to 12Gy had increased tumor
weight compared to the 2Gy group (p=0.036). Analysis of tumors by hematoxylin and eosin (H&E) staining
revealed greater hemorrhage and red blood cell (RBC) extravasation in the 12Gy group compared to the
2Gy group and control mice. However, immunohistochemistry (IHC) for collagen IV and endomucin did
not reveal any significant disruption of the endothelium. Analysis of apoptosis by TUNEL stain revealed
intermittent regions of markedly increased apoptosis in the 12Gy samples, yet there was no difference in
density of apoptosis in the tumor tissue between these regions and the other two groups. Neither high
nor low-dose RT had any effect on circulating tumor cells measured by blood luciferase activity.
Conclusions: Analysis of mouse tumors 24 hours after irradiation with high dose RT demonstrates early
differences in comparison to tumors treated with low dose RT and no RT, such as increased hemorrhage,
RBC extravasation and necrosis. These findings suggest functional disruption of tumor vasculature,
without any clear breakdown of the correlating endothelium on IHC. We believe the regions of early
apoptotic activity likely correlate to regions affected by functional disruption of the vasculature. Further
analysis with in-vivo imaging of tumor vasculature with contrast-enhanced ultrasound is ongoing.
(PS2-61) HIF-1α responds to radiation by activating unique targets to promote radiation resistance via
a tumor-cell autonomous mechanism. Minsi Zhang; Qiong Qiu; Hooney Min; Zhizhong Li; Diana Cardona;
Yan Ma; Amanda Nichols; Tracy Han; Lixia Luo; Thies Schroeder; Mark W. Dewhirst; Christopher B.
Newgard; Jeffrey C. Rathmell; and David G. Kirsch, Duke University, Durham, NC
Hypoxia is a major cause of radiation resistance, which leads to local recurrence after radiation
therapy (RT). While hypoxia can promote tumor cell survival post-RT because there is less oxygen to
generate DNA adducts which are hard to repair, whether signaling pathways triggered by hypoxia
contribute to radiation resistance is poorly understood. For example, intratumoral hypoxia can increase
hypoxia-inducible factor-1α (HIF-1α), which may regulate pathways that contribute to radiation
sensitization and radiation resistance. To clarify the role of HIF-1α in regulating tumor response to
radiation therapy, we deleted HIF-1α in a novel primary mouse model of STS with conditional activation
168 | P a g e
