In Vivo Imaging of Methionine Aminopeptidase II for Prostate Cancer Risk Stratification

Prostate cancer is one of the most common malignancies worldwide, yet limited tools exist for prognostic risk stratification of the disease. Identification of new biomarkers representing intrinsic features of malignant transformation and development of prognostic imaging technologies are critical fo...

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Published in:	Cancer research (Chicago, Ill.) Vol. 81; no. 9; pp. 2510 - 2521
Main Authors:	Xie, Jinghang, Rice, Meghan A, Chen, Zixin, Cheng, Yunfeng, Hsu, En-Chi, Chen, Min, Song, Guosheng, Cui, Liyang, Zhou, Kaixiang, Castillo, Jessa B, Zhang, Chiyuan A, Shen, Bin, Chin, Frederick T, Kunder, Christian A, Brooks, James D, Stoyanova, Tanya, Rao, Jianghong
Format:	Journal Article
Language:	English
Published:	United States 01-05-2021
Online Access:	Get full text
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Summary:	Prostate cancer is one of the most common malignancies worldwide, yet limited tools exist for prognostic risk stratification of the disease. Identification of new biomarkers representing intrinsic features of malignant transformation and development of prognostic imaging technologies are critical for improving treatment decisions and patient survival. In this study, we analyzed radical prostatectomy specimens from 422 patients with localized disease to define the expression pattern of methionine aminopeptidase II (MetAP2), a cytosolic metalloprotease that has been identified as a druggable target in cancer. MetAP2 was highly expressed in 54% of low-grade and 59% of high-grade cancers. Elevated levels of MetAP2 at diagnosis were associated with shorter time to recurrence. Controlled self-assembly of a synthetic small molecule enabled design of the first MetAP2-activated PET imaging tracer for monitoring MetAP2 activity . The nanoparticles assembled upon MetAP2 activation were imaged in single prostate cancer cells with post-click fluorescence labeling. The fluorine-18-labeled tracers successfully differentiated MetAP2 activity in both MetAP2-knockdown and inhibitor-treated human prostate cancer xenografts by micro-PET/CT scanning. This highly sensitive imaging technology may provide a new tool for noninvasive early-risk stratification of prostate cancer and monitoring the therapeutic effect of MetAP2 inhibitors as anticancer drugs. SIGNIFICANCE: This study defines MetAP2 as an early-risk stratifier for molecular imaging of aggressive prostate cancer and describes a MetAP2-activated self-assembly small-molecule PET tracer for imaging MetAP2 activity .
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 These authors contributed equally to this work. Author contributions: J.X., M.A.R, T.S. and J.R. designed and led the study. Z.C., Y.C., K.Z. and J.X. performed the probe synthesis and analysis. J.D.B. contributed tissue sections, TMAs, and data analysis. M.A.R. performed IHC staining. C.A.K. scored the TMAs. C.A.Z. performed statistical analysis of TMAs. J.X. performed the cell studies, microscope, and flow cytometry. G.S. and J.X. performed the TEM and DLS studies. E.-C.H. generated the knockdown cells. J.X., M.A.R. and L.C. generated the animal models. J.B.C., B.S. and F.T.C. organized and performed the radiochemical synthesis. J.X., M.C. and K.Z. performed the PET/CT imaging, biodistribution study and data analysis. J.X., M.A.R., T.S. and J.R. analyzed all the data, and wrote the manuscript with inputs from all co-authors.
ISSN:	0008-5472 1538-7445
DOI:	10.1158/0008-5472.CAN-20-2969