Alba Gonzalez-Junca1, Oliver Reiners1, Luis D Borrero-Garcia1, Denis Beckford-Vera2, Ann A Lazar3, William Chou1, Steve Braunstein1, Henry VanBrocklin2, Benjamin L Franc4, Mary Helen Barcellos-Hoff5. 1. Department of Radiation Oncology, School of Medicine, University of California, San Francisco, California. 2. Department of Radiology and Biomedical Imaging, University of California, San Francisco, California. 3. Helen Diller Family Comprehensive Cancer Center, School of Medicine, University of California, San Francisco, California; Division of Oral Epidemiology, School of Dentistry, University of California, San Francisco, California; Division of Biostatistics, School of Medicine, University of California, San Francisco, California. 4. Department of Radiology and Biomedical Imaging, University of California, San Francisco, California; Division of Oral Epidemiology, School of Dentistry, University of California, San Francisco, California; Department of Radiology, School of Medicine, Stanford University, Palo Alto, California. 5. Department of Radiation Oncology, School of Medicine, University of California, San Francisco, California; Helen Diller Family Comprehensive Cancer Center, School of Medicine, University of California, San Francisco, California. Electronic address: maryhelen.barcellos-hoff@ucsf.edu.
Abstract
PURPOSE: Transforming growth factor β (TGFβ) promotes cell survival by endorsing DNA damage repair and mediates an immunosuppressive tumor microenvironment. Thus, TGFβ activation in response to radiation therapy is potentially targetable because it opposes therapeutic control. Strategies to assess this potential in the clinic are needed. METHODS AND MATERIALS: We evaluated positron emission tomography (PET) to image 89Zr -fresolimumab, a humanized TGFβ neutralizing monoclonal antibody, as a means to detect TGFβ activation in intracranial tumor models. Pathway activity of TGFβ was validated by immunodetection of phosphorylated SMAD2 and the TGFβ target, tenascin. The contribution of TGFβ to radiation response was assessed by Kaplan-Meier survival analysis of mice bearing intracranial murine tumor models GL261 and SB28 glioblastoma and brain-adapted 4T1 breast cancer (4T1-BrA) treated with TGFβ neutralizing monoclonal antibody, 1D11, and/or focal radiation (10 Gy). RESULTS: 89Zr-fresolimumab PET imaging detected engineered, physiological, and radiation-induced TGFβ activation, which was confirmed by immunostaining of biological markers. GL261 glioblastoma tumors had a greater PET signal compared with similar-sized SB28 glioblastoma tumors, whereas the widespread PET signal of 4T1-BrA intracranial tumors was consistent with their highly dispersed histologic distribution. Survival of mice bearing intracranial tumors treated with 1D11 neutralizing antibody alone was similar to that of mice treated with control antibody, whereas 1D11 improved survival when given in combination with focal radiation. The extent of survival benefit of a combination of radiation and 1D11 was associated with the degree of TGFβ activity detected by PET. CONCLUSIONS: This study demonstrates that 89Zr-fresolimumab PET imaging detects radiation-induced TGFβ activation in tumors. Functional imaging indicated a range of TGFβ activity in intracranial tumors, but TGFβ blockade provided survival benefit only in the context of radiation treatment. This study provides further evidence that radiation-induced TGFβ activity opposes therapeutic response to radiation.
PURPOSE: Transforming growth factor β (TGFβ) promotes cell survival by endorsing DNA damage repair and mediates an immunosuppressive tumor microenvironment. Thus, TGFβ activation in response to radiation therapy is potentially targetable because it opposes therapeutic control. Strategies to assess this potential in the clinic are needed. METHODS AND MATERIALS: We evaluated positron emission tomography (PET) to image 89Zr -fresolimumab, a humanized TGFβ neutralizing monoclonal antibody, as a means to detect TGFβ activation in intracranial tumor models. Pathway activity of TGFβ was validated by immunodetection of phosphorylated SMAD2 and the TGFβ target, tenascin. The contribution of TGFβ to radiation response was assessed by Kaplan-Meier survival analysis of mice bearing intracranial murinetumor models GL261 and SB28glioblastoma and brain-adapted 4T1 breast cancer (4T1-BrA) treated with TGFβ neutralizing monoclonal antibody, 1D11, and/or focal radiation (10 Gy). RESULTS:89Zr-fresolimumabPET imaging detected engineered, physiological, and radiation-induced TGFβ activation, which was confirmed by immunostaining of biological markers. GL261glioblastoma tumors had a greater PET signal compared with similar-sized SB28glioblastoma tumors, whereas the widespread PET signal of 4T1-BrA intracranial tumors was consistent with their highly dispersed histologic distribution. Survival of mice bearing intracranial tumors treated with 1D11 neutralizing antibody alone was similar to that of mice treated with control antibody, whereas 1D11 improved survival when given in combination with focal radiation. The extent of survival benefit of a combination of radiation and 1D11 was associated with the degree of TGFβ activity detected by PET. CONCLUSIONS: This study demonstrates that 89Zr-fresolimumabPET imaging detects radiation-induced TGFβ activation in tumors. Functional imaging indicated a range of TGFβ activity in intracranial tumors, but TGFβ blockade provided survival benefit only in the context of radiation treatment. This study provides further evidence that radiation-induced TGFβ activity opposes therapeutic response to radiation.
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Authors: Naoki Takasaka; Robert I Seed; Anthony Cormier; Andrew J Bondesson; Jianlong Lou; Ahmed Elattma; Saburo Ito; Haruhiko Yanagisawa; Mitsuo Hashimoto; Royce Ma; Michelle D Levine; Jean Publicover; Rashaun Potts; Jillian M Jespersen; Melody G Campbell; Fraser Conrad; James D Marks; Yifan Cheng; Jody L Baron; Stephen L Nishimura Journal: JCI Insight Date: 2018-10-18
Authors: Giulia Petroni; Lewis C Cantley; Laura Santambrogio; Silvia C Formenti; Lorenzo Galluzzi Journal: Nat Rev Clin Oncol Date: 2021-11-24 Impact factor: 66.675