FAP PET identifies earlycardiac molecular changesinduced by doxorubicin chemotherapy
Chul-Hee Lee, Onorina L. Manzo, Luisa Rubinelli, Sebastian E. Carrasco, Sungyun Cho, Thomas M. Jeitner, John Babich, Annarita Di Lorenzo, James M. Kelly
Chul-Hee Lee, Onorina L. Manzo, Luisa Rubinelli, Sebastian E. Carrasco, Sungyun Cho, Thomas M. Jeitner, John Babich, Annarita Di Lorenzo, James M. Kelly
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Research Article Cardiology Therapeutics

FAP PET identifies earlycardiac molecular changesinduced by doxorubicin chemotherapy

Abstract

Anthracycline chemotherapy, widely used in cancer treatment, poses a significant risk of cardiotoxicity that results in functional decline. Current diagnostic methods poorly predict cardiotoxicity because they do not detect early damage that precedes dysfunction. Positron emission tomography (PET) is well suited to address this need when coupled with suitable imaging biomarkers. We used PET to evaluate cardiac molecular changes in male C57BL/6J mice exposed to doxorubicin (DOX). These mice initially developed cardiac atrophy, experienced functional deficits within 10 weeks of treatment, and developed cardiac fibrosis by 16 weeks. Elevated cardiac uptake of [68Ga]Ga-FAPI-04, a PET tracer targeting fibroblast activation protein α (FAP), was evident by 2 weeks and preceded the onset of functional deficits. Cardiac PET signal correlated with FAP expression and activity as well as other canonical indicators of cardiac remodeling. By contrast, cardiac uptake of [18F]DPA-714 and [18F]MFBG, which target translocator protein 18 kDa and the norepinephrine transporter, respectively, did not differ between the DOX animals and their controls. These findings identify FAP as an early imaging biomarker for DOX-induced cardiac remodeling in males and support the use of FAP PET imaging to detect some cancer patients at risk for treatment-related myocardial damage before cardiac function declines.

Authors

Chul-Hee Lee, Onorina L. Manzo, Luisa Rubinelli, Sebastian E. Carrasco, Sungyun Cho, Thomas M. Jeitner, John Babich, Annarita Di Lorenzo, James M. Kelly

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Figure 3

Early-stage FAP expression is detectable with [68Ga]Ga-FAPI-04 PET.

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Early-stage FAP expression is detectable with [68Ga]Ga-FAPI-04 PET. (A) ...
(A) Representative summed PET/CT fusion transaxial MIP images at 2 and 10 weeks after initial DOX exposure. Mice were imaged with [68Ga]Ga-FAPI-04 (top), [18F]DPA-714 (middle), or [18F]MFBG (bottom). Images were acquired 60 minutes postinjection. BAT, brown adipose tissue; H, heart; L, lung. (B) SUVmax of [68Ga]Ga-FAPI-04 in cardiac tissues at 2 and 10 weeks. (C) Quantitation of cardiac PET signals normalized to skeletal (calf) muscle uptake (heart/muscle ratio, H/M) at 2 and 10 weeks. (D) Comparison of image-derived cardiac uptake of [68Ga]Ga-FAPI-04, [18F]DPA-714, and [18F]MFBG over the time course of the experiment. Quantification of cardiac PET uptake of C and D was performed using AMIDE and normalized to skeletal (calf) muscle uptake. At least 3 mice were imaged at each time point, with the specific number reported in Supplemental Table 4. Data are presented as the mean ± SD. Statistical comparisons were performed using an unpaired 2-tailed t test, with Welch’s correction in D. *P < 0.05; **P < 0.01; ***P < 0.001. FAP, fibroblast activation protein α; NET, norepinephrine transporter; TSPO, translocator protein 18 kDa; SUVmax, maximum standardized uptake value; MIP, maximum intensity projection.