Abstract
INTRODUCTION: Transforming growth factor beta (TGFbeta) promotes cell survival by endorsing DNA damage repair and mediates an immunosuppressive tumor microenvironment. Thus, TGFbeta 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: & Materials: We evaluated positron emission tomography (PET) to image 89Zr -fresolimumab, a humanized TGFbeta neutralizing monoclonal antibody, as means to detect TGFbeta activation in intracranial tumor models. TGFbeta pathway activity was validated by immunodetection of phosphorylated SMAD2 and TGFbeta target, tenascin. The contribution of TGFbeta 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 TGFbeta neutralizing monoclonal antibody, 1D11, and/or focal radiation (10 Gy).RESULTS: 89Zr-fresolimumab PET imaging detected engineered, physiological and radiation-induced TGFbeta activation, which was confirmed by immunostaining of biological markers. GL261 glioblastoma tumors had more PET signal compared to similar sized SB28 glioblastoma tumors, whereas widespread PET signal of 4T1-BrA intracranial tumors is consistent with its highly dispersed histological 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 combination of radiation and 1D11 was associated with the degree of TGFbeta activity detected by PET.CONCLUSIONS: This study demonstrates that 89Zr -fresolimumab PET imaging detects radiation-induced TGFbeta activation in tumors. Functional imaging indicated a range of TGFbeta activity in intracranial tumors, but TGFbeta blockade provided survival benefit only in the context of radiation treatment. These studies are further evidence that radiation-induced TGFbeta activity opposes therapeutic response to radiation.
View details for DOI 10.1016/j.ijrobp.2020.09.043
View details for PubMedID 33007434