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Life sciences · Journal article
Frontiers in Genetics · September 17, 2026
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Drug repurposing represents a pragmatic strategy for patients with cancer who have limited standard-of-care options. Traditional in silico or functional repurposing approaches often rely on well-characterised protein targets or validated experimental models, which are sparsely available in rare cancer settings and impractical within clinically relevant timeframes. Tumour-agnostic biomarker-driven strategies, by contrast, offer more timely workflows for integration into routine oncology practice, but have largely been dominated by ‘on-target’ approaches that may be less applicable to rare cancers frequently lacking canonical targetable mutations. However, emerging pharmacological evidence demonstrates that many anticancer agents engage a broader target landscape, creating opportunities for ‘off-target’ repurposing against non-canonical tumour dependencies. Although less established, we contend ‘off-target’ repurposing remains a potentially important strategy offering therapeutic hope to patients with rare cancers for whom no standard options, targetable biomarkers, or disease-specific trials exist. This perspective explores emerging evidence surrounding ‘off-target’ repurposing as a strategy, as well as evaluating recent criticisms of off-target low-evidence genomic matching in precision oncology literature. By doing so, we advocate for development of rigorously designed prospective clinical trials to examine ‘off target’ strategies, centred in safety of participants, evidence generation, and accessibility. Such frameworks require embedding off-target candidates within trial designs suited to small heterogeneous cohorts, with built-in mechanisms for evidence generation and access to therapies. We propose safe implementation should incorporate longitudinal monitoring, and parallel orthogonal validation to strengthen biological and pharmacological plausibility, refine drug and dose selection, and inform adaptive treatment modification over time.