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Pyruvate Metabolism: A Therapeutic Opportunity in Radiation-Induced Skin Injury
E534
International Journal of Radiation Oncology Biology Physics
with PI-103 showed persistent gH2AX foci, indicating delayed repair of DNA strand breaks. PI-103 alone increased levels of poly(ADP-ribose) and phosphorylated extracellular signal-regulated kinase, and downregulated BRCA1. Conclusion: Combined use of olaparib and PI-103 enhanced radiationinduced cell death in BRCA-proficient MDA-MB-435S and MDA-MB231-BR cells and xenografts. TNBC patients have high incidences of locoregional relapse and distant metastasis, and radiation therapy targets both locoregional control and treatment of distant recurrences such as brain metastasis or other oligometastasis. Targeting of the PI3K signaling pathway combined with PARP inhibition maybe a feasible approach to enhance effects of radiation in BRCA-proficient TNBC. Work supported by grant (#2012-0004867 & #2013R1A1A2074531) from National Research Foundation, Korean Ministry of Future Creative Science to Kim IA. Author Disclosure: I. Kim: None. N. Jang: None. D. Kim: None. B. Cho: None. E. Choi: None.
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3338 Catheter Based Structural and Molecular Imaging of Prostate Cancer Using an Ultrasound/Photoacoustic Probe M. Sano,1 S. Yousefi,2 and L. Xing3; 1Stanford University School of Medicine, Radiation Oncology, Stanford, CA, 2Stanford University, Stanford, CA, 3Stanford University School of Medicine, Stanford, CA Purpose/Objective(s): The objective of this work is to design, implement and characterize a catheter-based ultrasound/photoacoustic imaging probe for early diagnosis of prostate cancer and to aid in image guided radiation therapy. Ultrasound is an inexpensive and widely adopted imaging modality which enables real-time imaging of the prostate in outpatient clinical settings. Transrectal probes with a center frequency of 3-5 MHz are typically employed. The resolution of the ultrasound system is directly related to the transducer frequency and higher frequency transducers produce higher resolution images. However, ultrasound penetration depth is inversely related to the transducer center frequency. Therefore, high-resolution deep tissue imaging of the prostate tissue is not currently achievable. Transrectal probes cannot uniformly image the prostate tissue with the same resolution/signal strength due to anatomical constraints. In particular, the need to image across the full depth of the prostate gland (6-10 cm) limits the resolution achievable. In contrast, the urethra bisects the prostate gland, providing a minimally invasive pathway for deploying a high resolution ultrasound transducer. Utilizing a high-frequency (20MHz) ultrasound/photoacoustic probe, high-resolution structural and molecular imaging of the prostate tissue is possible. Materials/Methods: To achieve high-resolution structural and molecular imaging of the prostate tissue, a high-frequency single-element ultrasound probe is utilized. The diameter of the probe is designed to fit inside a Foley catheter. To achieve circular B-scan, the probe is rotated around the central axis. A custom ultrasound amplifier and receiver were set up to trigger the ultrasound pulse transmission and record the reflected signal. The system is combined with a pulsed-laser and a passive ultrasound element is used to receive the photoacoustic signal. Results: The preliminary results using the high-frequency ultrasound probe show that it is possible to resolve finely detailed information in a prostate tissue phantom that was not achievable with previous low-frequency ultrasound systems. Preliminary ultrasound imaging was performed on tissue mimicking phantom and sensitivity and signal-to-noise ratio of the catheter was measured. Conclusion: In order to achieve non-invasive, high-resolution, structural and molecular imaging for early diagnosis and image guided radiation therapy of the prostate tissue, a transurethral catheter was designed. The catheter can be passed through a Foley catheter for clinical applications. Structural/molecular imaging using ultrasound/photoacoustic of the prostate tissue will allow for localization of hypervascularized areas for earlystage prostate cancer diagnosis. Author Disclosure: M. Sano: None. S. Yousefi: None. L. Xing: None.
Pyruvate Metabolism: A Therapeutic Opportunity in RadiationInduced Skin Injury H. Yoo,1 J.W. Kang,2 D.W. Lee,3 S.H. Oh,4 Y.S. Lee,5 E.J. Lee,6 J.M. Lee,2 and J.H. Cho2; 1Severance Hospital of the Yonsei University Health System, Seoul 120-752, Korea, Republic Of, 2Department of Radiation Oncology, Yonsei University College of Medicine, Seoul, South Korea, South Korea, 3Plastic Surgery, Yonsei University College of Medicine, Seoul, South Korea, South Korea, 4Dermatology, Yonsei University College of Medicine, Seoul, South Korea, South Korea, 5College of Pharmacy & Division of Life and Pharmaceutical Sciences, Ewah Women’s University, Seoul, South Korea, South Korea, 6Yonsei University Health System, Seoul, Korea, Republic Of Purpose/Objective(s): Ionizing radiation is used to treat a range of cancers. Despite recent technological progress, radiation therapy can damage the skin at the administration site. The specific molecular mechanisms involved in this effect have not been fully characterized. We explored the effects of radiation on gene expression and investigated whether oral pyruvate administration ameliorated radiation-induced skin damage in mice. Materials/Methods: Male adult C57BL/6 mice were exposed to a single radiation dose (50 Gy) to the dorsal skin using a 1-cm2 collimator. We examined mRNA expression using next generation sequencing (NGS), quantitative real-time polymerase chain reaction (Q-PCR), and performed immunohistochemical analyses of skin from mice that had received oral pyruvate (500 mg/kg), as compared with controls. Results: NGS identified a wide range of gene expression differences between the control and irradiated mice, including reduced expression of pyruvate dehydrogenase kinase 2 (PDK2). This was confirmed using Q-PCR. Cell culture studies demonstrated that PDK2 overexpression and a high cellular pyruvate concentration inhibited radiation-induced cytokine expression. Immunohistochemical studies demonstrated radiation-induced skin thickening and gene expression changes. Oral pyruvate produced a substantial reduction in both of these effects in mice. Conclusion: These findings indicated that regulation of the pyruvate metabolic pathway could provide an effective approach to the control of radiation-induced skin damage. Author Disclosure: H. Yoo: None. J. Kang: None. D. Lee: None. S. Oh: None. Y. Lee: None. E. Lee: None. J. Lee: None. J. Cho: None.
3340 LIMD1 Radiosensitizes Human Non-Small Cell Lung Cancer Cells Via Inhibiting NF-kB Signaling Z. Wu,1 M. Qiu,1 M. Meng,1 Y. Guo,2 D. Qian,1 Z. Yuan,1 H. Wang,1 and X. Zeng1; 1Department of Radiation therapy, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin, China, 2Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin, China Purpose/Objective(s): Radiation therapy achieved remarkable effects in the treatment of non-small cell lung cancer (NSCLC). However, to identify bio-makers that could predict or enhance radiosensitivity to improve outcomes of NSCLC patients remains urgent. LIMD1 was shown to be downregulated in NSCLC and plays pivotal roles in NSCLC development. However, whether LIMD1 was a potential target for enhancing radiosensitivity and the underling mechanisms remains unknown. This study aims at demonstrating LIMD1 to be a target for enhancing radiosensitivity and uncovering the underling mechanisms. Materials/Methods: Clonogenic assay was performed to analyze the effects of LIMD1 on radiosensitivity of NSCLC cells. FACS and immunofluorescence assays were applied to detect cell apoptosis and autophagic cell death. Luciferase reporter analysis, gene set enrichment analysis, Western blotting, qRT-PCR and Co-IP were applied to demonstrate that LIMD1 modulating NF-kB signaling.
International Journal of Radiation Oncology Biology Physics
with PI-103 showed persistent gH2AX foci, indicating delayed repair of DNA strand breaks. PI-103 alone increased levels of poly(ADP-ribose) and phosphorylated extracellular signal-regulated kinase, and downregulated BRCA1. Conclusion: Combined use of olaparib and PI-103 enhanced radiationinduced cell death in BRCA-proficient MDA-MB-435S and MDA-MB231-BR cells and xenografts. TNBC patients have high incidences of locoregional relapse and distant metastasis, and radiation therapy targets both locoregional control and treatment of distant recurrences such as brain metastasis or other oligometastasis. Targeting of the PI3K signaling pathway combined with PARP inhibition maybe a feasible approach to enhance effects of radiation in BRCA-proficient TNBC. Work supported by grant (#2012-0004867 & #2013R1A1A2074531) from National Research Foundation, Korean Ministry of Future Creative Science to Kim IA. Author Disclosure: I. Kim: None. N. Jang: None. D. Kim: None. B. Cho: None. E. Choi: None.
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3338 Catheter Based Structural and Molecular Imaging of Prostate Cancer Using an Ultrasound/Photoacoustic Probe M. Sano,1 S. Yousefi,2 and L. Xing3; 1Stanford University School of Medicine, Radiation Oncology, Stanford, CA, 2Stanford University, Stanford, CA, 3Stanford University School of Medicine, Stanford, CA Purpose/Objective(s): The objective of this work is to design, implement and characterize a catheter-based ultrasound/photoacoustic imaging probe for early diagnosis of prostate cancer and to aid in image guided radiation therapy. Ultrasound is an inexpensive and widely adopted imaging modality which enables real-time imaging of the prostate in outpatient clinical settings. Transrectal probes with a center frequency of 3-5 MHz are typically employed. The resolution of the ultrasound system is directly related to the transducer frequency and higher frequency transducers produce higher resolution images. However, ultrasound penetration depth is inversely related to the transducer center frequency. Therefore, high-resolution deep tissue imaging of the prostate tissue is not currently achievable. Transrectal probes cannot uniformly image the prostate tissue with the same resolution/signal strength due to anatomical constraints. In particular, the need to image across the full depth of the prostate gland (6-10 cm) limits the resolution achievable. In contrast, the urethra bisects the prostate gland, providing a minimally invasive pathway for deploying a high resolution ultrasound transducer. Utilizing a high-frequency (20MHz) ultrasound/photoacoustic probe, high-resolution structural and molecular imaging of the prostate tissue is possible. Materials/Methods: To achieve high-resolution structural and molecular imaging of the prostate tissue, a high-frequency single-element ultrasound probe is utilized. The diameter of the probe is designed to fit inside a Foley catheter. To achieve circular B-scan, the probe is rotated around the central axis. A custom ultrasound amplifier and receiver were set up to trigger the ultrasound pulse transmission and record the reflected signal. The system is combined with a pulsed-laser and a passive ultrasound element is used to receive the photoacoustic signal. Results: The preliminary results using the high-frequency ultrasound probe show that it is possible to resolve finely detailed information in a prostate tissue phantom that was not achievable with previous low-frequency ultrasound systems. Preliminary ultrasound imaging was performed on tissue mimicking phantom and sensitivity and signal-to-noise ratio of the catheter was measured. Conclusion: In order to achieve non-invasive, high-resolution, structural and molecular imaging for early diagnosis and image guided radiation therapy of the prostate tissue, a transurethral catheter was designed. The catheter can be passed through a Foley catheter for clinical applications. Structural/molecular imaging using ultrasound/photoacoustic of the prostate tissue will allow for localization of hypervascularized areas for earlystage prostate cancer diagnosis. Author Disclosure: M. Sano: None. S. Yousefi: None. L. Xing: None.
Pyruvate Metabolism: A Therapeutic Opportunity in RadiationInduced Skin Injury H. Yoo,1 J.W. Kang,2 D.W. Lee,3 S.H. Oh,4 Y.S. Lee,5 E.J. Lee,6 J.M. Lee,2 and J.H. Cho2; 1Severance Hospital of the Yonsei University Health System, Seoul 120-752, Korea, Republic Of, 2Department of Radiation Oncology, Yonsei University College of Medicine, Seoul, South Korea, South Korea, 3Plastic Surgery, Yonsei University College of Medicine, Seoul, South Korea, South Korea, 4Dermatology, Yonsei University College of Medicine, Seoul, South Korea, South Korea, 5College of Pharmacy & Division of Life and Pharmaceutical Sciences, Ewah Women’s University, Seoul, South Korea, South Korea, 6Yonsei University Health System, Seoul, Korea, Republic Of Purpose/Objective(s): Ionizing radiation is used to treat a range of cancers. Despite recent technological progress, radiation therapy can damage the skin at the administration site. The specific molecular mechanisms involved in this effect have not been fully characterized. We explored the effects of radiation on gene expression and investigated whether oral pyruvate administration ameliorated radiation-induced skin damage in mice. Materials/Methods: Male adult C57BL/6 mice were exposed to a single radiation dose (50 Gy) to the dorsal skin using a 1-cm2 collimator. We examined mRNA expression using next generation sequencing (NGS), quantitative real-time polymerase chain reaction (Q-PCR), and performed immunohistochemical analyses of skin from mice that had received oral pyruvate (500 mg/kg), as compared with controls. Results: NGS identified a wide range of gene expression differences between the control and irradiated mice, including reduced expression of pyruvate dehydrogenase kinase 2 (PDK2). This was confirmed using Q-PCR. Cell culture studies demonstrated that PDK2 overexpression and a high cellular pyruvate concentration inhibited radiation-induced cytokine expression. Immunohistochemical studies demonstrated radiation-induced skin thickening and gene expression changes. Oral pyruvate produced a substantial reduction in both of these effects in mice. Conclusion: These findings indicated that regulation of the pyruvate metabolic pathway could provide an effective approach to the control of radiation-induced skin damage. Author Disclosure: H. Yoo: None. J. Kang: None. D. Lee: None. S. Oh: None. Y. Lee: None. E. Lee: None. J. Lee: None. J. Cho: None.
3340 LIMD1 Radiosensitizes Human Non-Small Cell Lung Cancer Cells Via Inhibiting NF-kB Signaling Z. Wu,1 M. Qiu,1 M. Meng,1 Y. Guo,2 D. Qian,1 Z. Yuan,1 H. Wang,1 and X. Zeng1; 1Department of Radiation therapy, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin, China, 2Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin, China Purpose/Objective(s): Radiation therapy achieved remarkable effects in the treatment of non-small cell lung cancer (NSCLC). However, to identify bio-makers that could predict or enhance radiosensitivity to improve outcomes of NSCLC patients remains urgent. LIMD1 was shown to be downregulated in NSCLC and plays pivotal roles in NSCLC development. However, whether LIMD1 was a potential target for enhancing radiosensitivity and the underling mechanisms remains unknown. This study aims at demonstrating LIMD1 to be a target for enhancing radiosensitivity and uncovering the underling mechanisms. Materials/Methods: Clonogenic assay was performed to analyze the effects of LIMD1 on radiosensitivity of NSCLC cells. FACS and immunofluorescence assays were applied to detect cell apoptosis and autophagic cell death. Luciferase reporter analysis, gene set enrichment analysis, Western blotting, qRT-PCR and Co-IP were applied to demonstrate that LIMD1 modulating NF-kB signaling.