For more than 25 years, the NCI-60, a panel of 60 human cancer cell lines grown in vitro, has been conventionally used to test novel drugs for anticancer activity. These cell lines are relatively simple to culture compared to human xenografts, are inexpensive to grow and have contributed to much of our biological understanding of cancer. However, studies have shown that translating drug response findings from in vitro to patients has been challenging due to several reasons, including the selective pressure from in vitro culture which influences cell behaviours and affects drug response.
Advantages of PDC models in drug development
PDC models can help overcomes the challenges of traditional cell lines and PDX. Specifically, they are
- Faster to develop than any in vivo models. PDC models can be rapidly developed starting from patient biopsies and test results can be obtained within 3-4 weeks
- Maintain the original genetic make-up of the tumour while in culture, unlike classic cell lines
- As predictive of patient response as in vivo gold standard xenograft models with close to 90% rate of predicting a positive response and 100% of predictive a negative response
- Cost-effective
- Easier to scale than in vivo models allowing applications such as high-throughput screening and high-content imaging
- They can be used in personalised medicine approaches.
Have we reached the end of an era for cancer cell lines?
In 2016 the US National Cancer Institute (NCI) decided to retire the use of its NCI-60 panel of cell lines from its drug-screening program and replace it with models with a closer link to patients. Cell lines kept in culture for decades drift from the original tumour to the extent that it becomes impossible for any pathologist to recognise the tumour of origin. At the same time genomic analysis performed on panels of tumour cell lines showed that after many years of culture they resemble one another more than their tissue of origin and acquire genomic signatures adapted to the in vitro environment.
Patient-derived xenografts (PDXs) became the model of choice for the NCI and many others, including the EurOPDX consortium, the Jackson laboratories and big pharma companies such as Novartis. PDXs are freshly-resected cancer cells from patients which are transplanted and cultured into immunocompromised mice, and better preserves the original tumour genomic integrity and heterogeneity.
PDXs have since garnered media attention as possible models to guide treatment of individual patients, serving as ‘avatars’ to screen for the most-effective treatment regimen.
The need for in vitro patient relevant models
After some initial enthusiasm about conducting high throughput drug screening using PDXs, it soon became evident that the process of generating a PDX is too costly and slow to benefit the donor, therefore researchers have preferred to use PDXs in population studies to identify biomarkers of response instead. But this approach requires a large number of models and multiple test animals per study. This can be costly and time consuming.
There remains a need for an easily scalable, cryopreservable patient-derived model to perform large-scale drug testing for hit identification, lead validation, or to investigate mechanisms of action.
Patient-derived cell (PDC) models are tumour cells derived from patient biopsies which are grown in a well-defined medium and preserve in culture the original tumour identity.
These in vitro tumours are well characterised with NGS and in vitro drug response data to more than 60 approved standard of care drugs, in addition to patient clinical history and therapy response data.
Summary
PDC models are uniquely positioned among patient-derived models for their stability in culture, speed of development and applicability to personalised medicine with an already established in vitro diagnostic and drug screening platform.
