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Synthetic biomarkers: a twenty-first century path to early cancer detection

Abstract

Detection of cancer at an early stage when it is still localized improves patient response to medical interventions for most cancer types. The success of screening tools such as cervical cytology to reduce mortality has spurred significant interest in new methods for early detection (for example, using non-invasive blood-based or biofluid-based biomarkers). Yet biomarkers shed from early lesions are limited by fundamental biological and mass transport barriers — such as short circulation times and blood dilution — that limit early detection. To address this issue, synthetic biomarkers are being developed. These represent an emerging class of diagnostics that deploy bioengineered sensors inside the body to query early-stage tumours and amplify disease signals to levels that could potentially exceed those of shed biomarkers. These strategies leverage design principles and advances from chemistry, synthetic biology and cell engineering. In this Review, we discuss the rationale for development of biofluid-based synthetic biomarkers. We examine how these strategies harness dysregulated features of tumours to amplify detection signals, use tumour-selective activation to increase specificity and leverage natural processing of bodily fluids (for example, blood, urine and proximal fluids) for easy detection. Finally, we highlight the challenges that exist for preclinical development and clinical translation of synthetic biomarker diagnostics.

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Fig. 1: Challenges associated with detecting early-stage tumours.
Fig. 2: Activity-based synthetic biomarkers enrich tumour protease signatures.
Fig. 3: Small-molecule probes sense tumour-associated enzymatic activity.
Fig. 4: Genetically encoded synthetic biomarkers leverage tumour-specific cues to achieve detectable signals.
Fig. 5: Characteristics of synthetic biomarkers for early-stage cancer detection.

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Acknowledgements

The US National Cancer Institute organized the Synthetic Biomarkers for Detection of Cancers at Incipient and Early Stages (SYNDICATE) Think Tank Meeting in 2019, where bioengineers, biologists and clinicians discussed the promises and challenges of synthetic biomarkers from development to preclinical models to scale up to meeting the ultimate goal of safe use in the clinic. The authors express their gratitude to all SYNDICATE meeting participants for their thoughts, expertise and insightful comments. They thank T. Danino (Columbia University) and L. Chan (Georgia Tech & Emory University) for insightful discussions. This work was funded by the US NIH Director’s New Innovator Award (DP2HD091793) and the National Cancer Institute R01 grant 5R01CA237210 to G.A.K. S.N.B. is a Howard Hughes Medical Institute investigator. L.G. was supported by the US National Science Foundation Graduate Research Fellowship Program (DGE-1451512). This work was performed in part at the Georgia Tech Institute for Electronics and Nanotechnology, a member of the National Nanotechnology Coordinated Infrastructure, which is supported by the National Science Foundation (grant ECCS-1542174). This content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.

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G.A.K., S.G., L.G., S.S. and S.N.B. researched the data for the article, provided substantial contributions to discussions of the content and contributed to writing the article. G.A.K., S.G., L.G., C.P., S.S. and S.N.B. reviewed and/or edited the manuscript before submission.

Corresponding authors

Correspondence to Gabriel A. Kwong, Sharmistha Ghosh, Sudhir Srivastava or Sangeeta N. Bhatia.

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Competing interests

G.A.K. is a co-founder of Glympse Bio, and consults for Glympse Bio and Satellite Bio. S.N.B. is a director of Vertex, is a co-founder of and consultant for Glympse Bio, Satellite Bio and CEND Therapeutics, is a consultant for Moderna, and receives sponsored research funds from Johnson & Johnson. S.G., C.P., S.S. and L.G. declare no conflicts of interest.

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Dedication

This article is dedicated to the late Dr Sanjiv Sam Gambhir, a visionary pioneer and thought leader in bioengineering who devoted his career to developing methods for early disease detection.

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Nature Reviews Cancer thanks the anonymous reviewers for their contribution to the peer review of this work.

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Glossary

Multicompartment models

A mathematical modelling technique whereby distinct compartments are used to represent organs, tissues, blood or lymph to predict how an administered drug is absorbed, distributed, metabolized or excreted.

Hydrodynamic radius

For a macromolecule in solution, the radius of an equivalent hard sphere diffusing at the same rate as the macromolecule.

Deuterated metabolite

A compound in which one or more hydrogen atoms have been replaced by the stable isotope deuterium to distinguish it from its unmodified counterpart.

Bio-orthogonal reporters

Non-native reporters that do not interfere with biological functions.

Herpes simplex virus 1 thymidine kinase

(HSV1-TK). The enzyme expressed by the reporter gene phosphorylates radiolabelled purine and pyrimidine nucleoside analogues to trap the probe within cells and thereby allow visualization by positron emission tomography (PET).

AND gate

A Boolean logic gate operation that outputs a value of 1 if and only if both inputs are 1; otherwise it outputs 0.

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Kwong, G.A., Ghosh, S., Gamboa, L. et al. Synthetic biomarkers: a twenty-first century path to early cancer detection. Nat Rev Cancer 21, 655–668 (2021). https://doi.org/10.1038/s41568-021-00389-3

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