Positron Emission Tomography Imaging of Functional Transforming Growth Factor ß (TGFß) Activity and Benefit of TGFß Inhibition in Irradiated Intracranial Tumors.

ABSTRACT

PURPOSE: Transforming growth factor ß (TGFß) promotes cell survival by endorsing DNA damage repair and mediates an immunosuppressive tumor microenvironment. Thus, TGFß 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 TGFß neutralizing monoclonal antibody, as a means to detect TGFß activation in intracranial tumor models. Pathway activity of TGFß was validated by immunodetection of phosphorylated SMAD2 and the TGFß target, tenascin. The contribution of TGFß 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 TGFß neutralizing monoclonal antibody, 1D11, and/or focal radiation (10 Gy). RESULTS: 89Zr-fresolimumab PET imaging detected engineered, physiological, and radiation-induced TGFß 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 TGFß activity detected by PET. CONCLUSIONS: This study demonstrates that 89Zr-fresolimumab PET imaging detects radiation-induced TGFß activation in tumors. Functional imaging indicated a range of TGFß activity in intracranial tumors, but TGFß blockade provided survival benefit only in the context of radiation treatment. This study provides further evidence that radiation-induced TGFß activity opposes therapeutic response to radiation.