Dataset Information

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

ABSTRACT:

Purpose

Transforming growth factor ? (TGF?) promotes cell survival by endorsing DNA damage repair and mediates an immunosuppressive tumor microenvironment. Thus, TGF? 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 TGF? neutralizing monoclonal antibody, as a means to detect TGF? activation in intracranial tumor models. Pathway activity of TGF? was validated by immunodetection of phosphorylated SMAD2 and the TGF? target, tenascin. The contribution of TGF? 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 TGF? neutralizing monoclonal antibody, 1D11, and/or focal radiation (10 Gy).

Results

⁸⁹Zr-fresolimumab PET imaging detected engineered, physiological, and radiation-induced TGF? 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 TGF? activity detected by PET.

Conclusions

This study demonstrates that ⁸⁹Zr-fresolimumab PET imaging detects radiation-induced TGF? activation in tumors. Functional imaging indicated a range of TGF? activity in intracranial tumors, but TGF? blockade provided survival benefit only in the context of radiation treatment. This study provides further evidence that radiation-induced TGF? activity opposes therapeutic response to radiation.

SUBMITTER: Gonzalez-Junca A

PROVIDER: S-EPMC7856163 | biostudies-literature | 2021 Feb

REPOSITORIES: biostudies-literature

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

Gonzalez-Junca Alba A Reiners Oliver O Borrero-Garcia Luis D LD Beckford-Vera Denis D Lazar Ann A AA Chou William W Braunstein Steve S VanBrocklin Henry H Franc Benjamin L BL Barcellos-Hoff Mary Helen MH

International journal of radiation oncology, biology, physics 20200929 2

<h4>Purpose</h4>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.<h4>Methods and materials</h4>We evaluated positron emission tomography (PET) to image <sup>89</sup>Zr -fresolimumab, a humanized TGFβ neutralizing monocl ...[more]

PMID: 33007434

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