Early drug discovery methods for cancer relied on phenotypic screening compared to the current molecularly driven methods of targeting tumor-specific pathways. However, druggable targets are still lacking for some cancers, and knowledge about the tumor pathways does not translate to therapeutic efficacy.
In a recent review published in Trends in Pharmacological Sciences, researchers discussed the niche areas in which phenotypic screening continues to be advantageous over the targeted approach and the recent advances in phenotypic screening technology that have increased their efficiency.
Study: Innovating cancer drug discovery with refined phenotypic screens. Image Credit: paulista/Shutterstock.com
Phenotypic Screening
Phenotypic screening aims to identify biological or chemical compounds that induce specific alterations in biological systems. The earliest cancer drugs were discovered through phenotypic screening before the molecular mechanisms and pathways of cancer were understood.
Unlike the targeted approach, phenotypic screening considers knowledge about the drug target a bias. It follows a black-box approach, which avoids prior knowledge about the drug targets or its mechanism of action.
While the shift to targeted drug discovery and the focus on the molecular pathways and processes underlying cancer has indeed resulted in the discovery of numerous novel cancer drugs, phenotypic screening retains its importance in a drug-discovery niche due to the shortcomings of the targeted approach.
Furthermore, advances in phenotypic screening technology, such as organoid development, have expanded the method's applications and improved its efficiency.
The present review discussed the continuing importance of phenotypic screening in contemporary cancer research. The authors also examined the progress made in improving discovery power, refining readouts, and developing disease-relevant biological models.
Advantages of Phenotypic Screening
Despite the significant strides made in cancer drug discovery through the targeted approach, some limitations exist to the target-driven strategies and focus only on the molecular mechanisms linking the inhibition of these targets and the therapeutic outcomes.
The proposal of a potential target for therapy often occurs before adequate research has been conducted to understand the complete cellular context of the target. This presents downstream challenges in the actual success of the drug in aspects related to feedback, redundancy, crosstalk, and resistance.
Phenotypic screening focuses on the overall outcomes and is not constrained by the emphasis on molecular pathways, providing a more cost-effective alternative.
Furthermore, for cancers lacking obvious molecular targets, phenotypic screening continues to be the better approach for drug discovery. Osteosarcomas and triple-negative breast cancer (TNBC) are examples where phenotypic screening has helped discover viable drugs.
The lack of targets, such as human epidermal growth factors and estrogen and progesterone receptors in TNBC, has made the use of targeted drug discovery difficult for this form of cancer.
However, phenotypic screening used cell viability readouts to identify tinengotinib, which showed broad-spectrum kinase action.
Similarly, thiazolidinone was also discovered through phenotypic screening to have nanomolar killing efficacy, which was effective against osteosarcomas.
Phenotypic screening also makes it possible to screen large drug combination panels for cancers that have poor prognoses. The method can also be used to screen various naturally occurring biological compounds that lack established targets.
This method helped identify the efficacy of harmine in inhibiting cellular proliferation in TNBC. Drugs previously approved for other diseases can also be screened and repurposed for various cancers using phenotypic screening.
Recent Innovations in Phenotypic Screening
Advances along various technological avenues have helped improve phenotypic screening methods and address many of the shortcomings of the targeted approach to drug development.
The review discussed the technological advances that have helped address drug resistance, the failure of potential drugs during clinical trials, and the development of disease-relevant biological cancer models using phenotypic screening.
Using comprehensive and diverse cell panels, such as the 60 human cell line panel developed by the National Cancer Institute, can help identify drug-resistant cancer phenotypes early on in the drug discovery pipeline.
Furthermore, phenotypic screening allows a broad range of cancer genotypes to be screened, improving the probability of detecting potential mechanisms of drug resistance.
Organoids derived from patient’s cells have been a game-changing innovation in phenotypic screening by allowing the heterogeneity and microenvironment of cancer to be replicated and studied ex vivo.
Biobanks of bladder, breast, gastrointestinal, and colorectal cancer organoids have made it possible to refine drug screening using cytotoxicity readouts.
Conclusions
Overall, the review provided a strong case for why phenotypic screening is an important drug development avenue despite the advances in the targeted approach using tumor-specific pathways.
The researchers presented a comprehensive argument about the shortcomings of the targeted approach and the recent advancements in phenotypic screening that have helped address these shortcomings in drug development.
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