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Proc Natl Acad Sci U S A. 2015 Mar 10;112(10):3068-73. doi: 10.1073/pnas.1414156112. Epub 2015 Feb 23.

Detecting cancers through tumor-activatable minicircles that lead to a detectable blood biomarker.

Author information

1
Molecular Imaging Program at Stanford, Stanford University, Stanford, CA, 94305; Department of Radiology, Stanford University School of Medicine, Stanford, CA 94305;
2
Molecular Imaging Program at Stanford, Stanford University, Stanford, CA, 94305; Department of Biomedical Imaging and Radiological Sciences, National Yang-Ming University, Taipei, 112 Taiwan; and.
3
Molecular Imaging Program at Stanford, Stanford University, Stanford, CA, 94305; Department of Radiology, Stanford University School of Medicine, Stanford, CA 94305; Canary Center at Stanford for Cancer Early Detection, Palo Alto, CA 94304.
4
Molecular Imaging Program at Stanford, Stanford University, Stanford, CA, 94305; Department of Radiology, Stanford University School of Medicine, Stanford, CA 94305; Canary Center at Stanford for Cancer Early Detection, Palo Alto, CA 94304 sgambhir@stanford.edu.

Abstract

Earlier detection of cancers can dramatically improve the efficacy of available treatment strategies. However, despite decades of effort on blood-based biomarker cancer detection, many promising endogenous biomarkers have failed clinically because of intractable problems such as highly variable background expression from nonmalignant tissues and tumor heterogeneity. In this work we present a tumor-detection strategy based on systemic administration of tumor-activatable minicircles that use the pan-tumor-specific Survivin promoter to drive expression of a secretable reporter that is detectable in the blood nearly exclusively in tumor-bearing subjects. After systemic administration we demonstrate a robust ability to differentiate mice bearing human melanoma metastases from tumor-free subjects for up to 2 wk simply by measuring blood reporter levels. Cumulative change in reporter levels also identified tumor-bearing subjects, and a receiver operator-characteristic curve analysis highlighted this test's performance with an area of 0.918 ± 0.084. Lung tumor burden additionally correlated (r(2) = 0.714; P < 0.05) with cumulative reporter levels, indicating that determination of disease extent was possible. Continued development of our system could improve tumor detectability dramatically because of the temporally controlled, high reporter expression in tumors and nearly zero background from healthy tissues. Our strategy's highly modular nature also allows it to be iteratively optimized over time to improve the test's sensitivity and specificity. We envision this system could be used first in patients at high risk for tumor recurrence, followed by screening high-risk populations before tumor diagnosis, and, if proven safe and effective, eventually may have potential as a powerful cancer-screening tool for the general population.

KEYWORDS:

blood test; cancer; minicircles; reporter gene; tumor-specific promoter

PMID:
25713388
PMCID:
PMC4364239
DOI:
10.1073/pnas.1414156112
[Indexed for MEDLINE]
Free PMC Article

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