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

Kwong, Gabriel A.; Ghosh, Sharmistha; Gamboa, Lena; Patriotis, Christos; Srivastava, Sudhir; Bhatia, Sangeeta N.

doi:10.1038/s41568-021-00389-3

Cited by 104 publications

(78 citation statements)

References 165 publications

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“…The rising incidence of cancer coupled with the high mortality rates highlights the need for new and more effective treatments in oncology. However, the outcome of anticancer treatments significantly depends on the extent of tumor disease at treatment initiation, which further highlights the relevance of preventive strategies as well as diagnostic procedures or other clinical interventions to allow early diagnosis of cancer and timely treatment initiation ( Kwong et al, 2021 ; Okoli et al, 2021 ). With respect to the development of novel anticancer drugs, there is a continuous effort to define the most accurate methods as well as the relevant endpoints to assess the clinical benefit of new compounds in the context of different tumors ( Daniele et al, 2020 ).…”

Section: Introductionmentioning

confidence: 99%

Local Investigators Significantly Overestimate Overall Response Rates Compared to Blinded Independent Central Reviews in Uncontrolled Oncology Trials: A Comprehensive Review of the Literature

Russo

Navarra

2022

Front. Pharmacol.

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Several drugs gained market authorization based on the demonstration of improved progression-free survival (PFS), adopted as a primary endpoint in Phase 3 clinical trials. In addition, an increasing number of drugs have been granted accelerated approval, and sometimes regular approval, by the main regulatory agencies based on the evaluation of the overall response rate in Phase 1 and 2 clinical trials. However, while the overall survival is an unbiased measure of drug efficacy, these outcomes rely on the assessment of radiological images and patients’ categorization using standardized response criteria. The evaluation of these outcomes may be influenced by subjective factors, particularly when the analysis is performed locally. In fact, blinding of treatment is not always possible in modern oncology trials. Therefore, a blinded independent central review is often adopted to overcome the problem of expectation bias associated with local investigator assessments. In this regard, we have recently observed that local investigators tend to overestimate the overall response rate in comparison to central reviewers in Phase 2 clinical trials, whereas we did not find any significant evaluation bias between local investigators and central reviews when considering progression-free survival in both Phase 2 and 3 trials. In the present article, we have tried to understand the reasons behind this discrepancy by reviewing the available evidence in the literature. In addition, a further analysis of Phase 2 and 3 clinical trials that included the evaluation of both endpoints showed that local investigators significantly overestimate overall response rates compared to blinded independent central reviews in uncontrolled oncology trials.

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Section: Introductionmentioning

confidence: 99%

Local Investigators Significantly Overestimate Overall Response Rates Compared to Blinded Independent Central Reviews in Uncontrolled Oncology Trials: A Comprehensive Review of the Literature

Russo

Navarra

2022

Front. Pharmacol.

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“…Upon proteolytic cleavage of the linker, the hairpin prodrug is unlocked to release free AMP (Fig 3A ). To measure OmpT activity, we synthesized an activity probe (McCarter et al , 2004 ; Kwong et al , 2013 , 2021 ; Holt et al , 2017 , 2018 ; Mac et al , 2019 ; Zhuang et al , 2019 ) with free linker peptides containing a fluorophore‐quencher pair, which produced an increase in fluorescence upon proteolytic cleavage. To demonstrate linker specificity for OmpT, we incubated the activity probe with OmpT genetic knockout bacteria, as well as the parent background strain ( E. coli K‐12 BW25113), and only observed activity in samples incubated with the parent strain (i.e., OmpT‐positive) (Fig 3B ).…”

Section: Resultsmentioning

confidence: 99%

Dimensionless parameter predicts bacterial prodrug success

Holt

Tuttle

et al. 2022

Molecular Systems Biology

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Understanding mechanisms of antibiotic failure is foundational to combating the growing threat of multidrug‐resistant bacteria. Prodrugs—which are converted into a pharmacologically active compound after administration—represent a growing class of therapeutics for treating bacterial infections but are understudied in the context of antibiotic failure. We hypothesize that strategies that rely on pathogen‐specific pathways for prodrug conversion are susceptible to competing rates of prodrug activation and bacterial replication, which could lead to treatment escape and failure. Here, we construct a mathematical model of prodrug kinetics to predict rate‐dependent conditions under which bacteria escape prodrug treatment. From this model, we derive a dimensionless parameter we call the Bacterial Advantage Heuristic ( BAH ) that predicts the transition between prodrug escape and successful treatment across a range of time scales (1–10 4 h), bacterial carrying capacities (5 × 10 4 –10 5 CFU/µl), and Michaelis constants ( K M = 0.747–7.47 mM). To verify these predictions in vitro , we use two models of bacteria‐prodrug competition: (i) an antimicrobial peptide hairpin that is enzymatically activated by bacterial surface proteases and (ii) a thiomaltose‐conjugated trimethoprim that is internalized by bacterial maltodextrin transporters and hydrolyzed by free thiols. We observe that prodrug failure occurs at BAH values above the same critical threshold predicted by the model. Furthermore, we demonstrate two examples of how failing prodrugs can be rescued by decreasing the BAH below the critical threshold via (i) substrate design and (ii) nutrient control. We envision such dimensionless parameters serving as supportive pharmacokinetic quantities that guide the design and administration of prodrug therapeutics.

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“…To overcome some of the challenges associated with cancer biomarkers, such as low sensitivity or specificity and technical limitations, a new class of synthetic biomarkers is being developed (reviewed in Reference [ 124 ]). The theory behind activity-based synthetic biomarkers is to administer an exogenous agent that includes a bioengineered sensor component.…”

Section: Techniques Used To Detect Molecular Cancer Biomarkersmentioning

confidence: 99%

Molecular Biomarkers in Cancer

2022

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Molecular cancer biomarkers are any measurable molecular indicator of risk of cancer, occurrence of cancer, or patient outcome. They may include germline or somatic genetic variants, epigenetic signatures, transcriptional changes, and proteomic signatures. These indicators are based on biomolecules, such as nucleic acids and proteins, that can be detected in samples obtained from tissues through tumor biopsy or, more easily and non-invasively, from blood (or serum or plasma), saliva, buccal swabs, stool, urine, etc. Detection technologies have advanced tremendously over the last decades, including techniques such as next-generation sequencing, nanotechnology, or methods to study circulating tumor DNA/RNA or exosomes. Clinical applications of biomarkers are extensive. They can be used as tools for cancer risk assessment, screening and early detection of cancer, accurate diagnosis, patient prognosis, prediction of response to therapy, and cancer surveillance and monitoring response. Therefore, they can help to optimize making decisions in clinical practice. Moreover, precision oncology is needed for newly developed targeted therapies, as they are functional only in patients with specific cancer genetic mutations, and biomarkers are the tools used for the identification of these subsets of patients. Improvement in the field of cancer biomarkers is, however, needed to overcome the scientific challenge of developing new biomarkers with greater sensitivity, specificity, and positive predictive value.

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

Cited by 104 publications

References 165 publications

Local Investigators Significantly Overestimate Overall Response Rates Compared to Blinded Independent Central Reviews in Uncontrolled Oncology Trials: A Comprehensive Review of the Literature

Local Investigators Significantly Overestimate Overall Response Rates Compared to Blinded Independent Central Reviews in Uncontrolled Oncology Trials: A Comprehensive Review of the Literature

Dimensionless parameter predicts bacterial prodrug success

Molecular Biomarkers in Cancer

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