Clinically-oriented phenotypic screening: understanding and exploiting the dynamic nature of the cancer cell phenotype
Understanding the cancer cell phenotype is central to both cancer diagnosis and treatment. Discrete molecular signatures among cancer phenotypes underpin patient stratification, while rapid methods for detailed phenotyping in the clinic (via liquid biopsies and tumour imaging) enable the delivery of personalised, effective precision medicines to the cancer patient…
Here, briefly, we describe how emerging data are defining molecular phenotypes among specific cancer cell lineages, and how these can be used in phenotypic screening to discover and profile drugs which modulate them. We focus on recent advances in molecular phenotyping for human glioma and its high-grade counterpart, glioblastoma multiforme (GBM), and review how laboratory advances for glioma are translating to the clinic.
Phenotypic screening systems underpin much of cancer drug discovery, with assays measuring proliferation, differentiation and other phenotypes forming a basis for reliably delivering new first-in-class drugs to the patient.1 In the literature, discussions have focused on the relative success of phenotypic drug discovery (PDD) compared to target-based drug discovery (TDD).2,3 However, the debate is now shifting to translating PDD screens from the lab to the clinic.4,5 In the lab, discussion centres on the authenticity of the cell and tissue systems being used for drug screening, but in the clinic, the key issues are the definition, validation and therapeutic utility of the phenotypic endpoints themselves.
Cancer-derived cell and animal models, and the human cancer phenotypes they recapitulate have long been the workhorse for studies of cancer drugs’ mode of action, efficacy and selectivity. Established cell lines provide robust and readily accessible cellular reagents for technology assessment, tool development and pathway analysis, and they continue to be used as the first port of call for initial translation of TDD ‘lead’ compounds into well-characterised cellular contexts.
Where established cancer cell lines can fail, however, is in clinically-relevant, disease-related hypothesis testing. The use of established cancer cell lines in this area, especially those that have been cultured for decades in artificial media containing high levels of growth factors and other serum components, comes with many caveats.6 Many established cell lines in routine use as cancer models have become ‘addicted’ to their ex vivo growth conditions, having acquired mutations that favour their growth and propagation under these unnatural laboratory conditions, making them in practice a poor surrogate for disease in situ.7
To mitigate these concerns, several new cell-based platforms have been established for use in phenotypic screening campaigns for glioma.8 Some of these, such as the Human Glioblastoma Cell Culture (HGCC) resource, comprise recently derived, well-characterised and clinically-annotated glioma cell lines representing all the tumour cell lineages present in glioma and glioblastoma patients, and are publicly available.9 Crucially, the basic process for producing authentic patient-derived cell systems for phenotypic screening at point-of-care is now well established.