RT Journal Article
SR Electronic
T1 Noninvasive measurement of mTORC1 signaling with transferrin based PET: from bench to bedside
JF Journal of Nuclear Medicine
JO J Nucl Med
FD Society of Nuclear Medicine
SP 390
OP 390
VO 58
IS supplement 1
A1 Michael Evans
A1 Charles Truillet
A1 Matthew Parker
A1 Loc Huynh
A1 Davide Ruggero
A1 Rahul Aggarwal
A1 Spencer Behr
A1 Jason Lewis
YR 2017
UL http://jnm.snmjournals.org/content/58/supplement_1/390.abstract
AB 390Objectives: Developing imaging tools that selectively measure the activity of central oncogenes could revolutionize cancer diagnosis and management. We aimed to develop the first imaging tool for PET that can measure the activity of mTORC1, one of the most important drivers of cancer.Methods: The relationship between mTORC1 signaling, transferrin receptor expression, and transferrin uptake was studied by genetically and pharmacologically manipulating mTORC1 activity in human glioma and prostate cancer cell lines in vitro. In vivo, 89Zr-labeled transferrin was used to study mTORC1 signaling in mice bearing human xenografts. 68Ga-labeled transferrin was used to study mTORC1 signaling in patients with castration resistant prostate cancer as part of a single center study at UCSF.Results: Genetic or pharmacological manipulations that activate mTORC1 increase transferrin uptake into cancer cells, while mTORC1 inhibition results in decreased transferrin uptake. The pharmacodynamics of mTORC1 inhibitors can also be measured with 89Zr-transferrin in mouse models. Lastly, 68Ga-transferrin detected ~75% of lesions in an 8 patient cohort.Conclusion: Transferrin receptor expression and transferrin uptake into cancer cells correlates positively with intracellular mTORC1 activity. Pharmacologically induced changes in mTORC1 activity can be measured in animal models with 89Zr-transferrin, and castration resistant prostate cancer, a disease known to harbor frequent mTORC1 activity, is very avid for 68Ga-transferrin. Collectively, these results promote use of transferrin-based PET to study mTORC1 signaling dynamics in clinically relevant animal models and man. Research Support: National Cancer Institute (R00CA172695, R01 176671), the Prostate Cancer Foundation, Department of Defense Congressionally Directed Medical Research Program, UCSF Academic Senate