Editors' ChoiceCancer

Taking cancer drug screening very personally

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Science Translational Medicine  30 Nov 2016:
Vol. 8, Issue 367, pp. 367ec190
DOI: 10.1126/scitranslmed.aal2799

The continued push towards precision oncology stems from the toxicities incurred by untailored use of chemotherapies and modest clinical inroads achieved from genetic signatures and patient-specific biomarkers. Although the use of patient-derived xenografts in preclinical models offers promise, technical challenges and variable predictive accuracies limit widespread adoption of this approach.

Yaari et al. devised a clever nanoparticle (NP)–based strategy that seeks to convert each patient into his or her own personal drug screening laboratory. Specifically, they exploit the cargo-carrying capacity of liposomal nanoformulations and enhanced permeability and retention (EPR) effects for tumor targeting. The researchers loaded various cytotoxins, caffeine, or placebo alongside DNA sequences, or barcodes, unique to each payload. As proof-of-concept, a cocktail of barcoded NPs was injected intravenously into murine models 48 hours before biopsy of tumor tissue. Total doses of injected NPs never exceeded 1/1000th of the therapeutic dose, thereby limiting systemic effects. Procured cells were sorted by viability status (live or dead), followed by barcode extraction, amplification, and sequencing to validate specificity. Drug activity, or lack thereof, within biopsies was defined by the presence of corresponding barcodes in dead (active) or live (inactive) cells. Screening results were confirmed by a subsequent treatment protocol.

The reported platform provides a launching point to expand its translational reach. The standard core biopsy should yield ample cells to test the efficacy of dozens, if not hundreds, of drugs. Multidrug treatment is often used clinically without quantitative appreciation for each chemotherapy’s contribution; the approach here could help inform optimal combinations. This proof-of-concept work only focused on preclinical biopsies. Yet, the minute drug amounts within barcoded NPs align with microdosing (Phase 0; < 1/100th the therapeutic dose) studies approved for human testing. In its current iteration, the approach relies on EPR effects through which less than 1% of injected NPs reach tumors. Exploiting active NP targeting could improve uptake efficiency, resulting in lower dosing requirements or broader barcode coverage. Beyond standard chemotherapies, the approach could help screen the biodistribution of different nanoformulations emerging from pharmaceutical pipelines. Taking it personally may have its perks after all.

Z. Yaari et al., Theranostic barcoded nanoparticles for personalized cancer medicine. Nat. Commun. 10.1038/ncomms13325 (2016). [Full Text]

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