Published in partnership with BioReperia
1. Defining the problem: challenges in cancer drug development
Due to the highly advanced nature of many modern cancer treatments, the pharmaceutical industry has been presented with a significant drug discovery challenge: to successfully select the most reliable, translational in-vivo models for the preclinical testing of new oncology therapies. In recent years especially, the preclinical testing phase of drug development has come to require far more sophisticated modelling techniques, in an effort to enable earlier identification of truly promising drug candidates, whilst simultaneously screening out those unlikely to ultimately reach clinical approval. Many models are now designed to provide a better mimicry of real-life patient environments, including more accurate genomic profiling, better tumour microenvironment simulation and more advanced immunological involvement, however these developments are still a work in progress.
In addition, the rise of precision medicine has highlighted the value of being able to accurately predict individual patient responses to cancer drugs, particularly as a common cause behind the failure of many clinical trials is linked to the fact that only a minority of patients respond to the drug in question. This typically relates to the diversity in genetic backgrounds seen across clinical trial patients, which correlates directly to the variety of drug responses observed during testing. With oncology currently holding one of the highest preclinical to clinical drug failure rates at 95%, understanding how to adopt a more individualised approach to clinical study design is an important step towards enabling more accurate matching of cancer patients to the right therapies.
However, successfully executing this idea of patient stratification remains a major challenge in many areas of drug development today, particularly due to the inaccuracy of preclinical models that are suboptimal for a given study, as well as the notable financial and time constraints that are often involved in the process.
2. Zebrafish modelling as a solution
BioReperia’s ‘ZTX™ ONCOLEADS’ platform presents a unique new solution to the above- described problems, by supplying an agile and highly customisable model for drug discovery and development projects that can be used for efficacy studies on all types of solid cancers.
By using zebrafish embryos as a model system, BioReperia has developed an advanced in-vivo platform that provides highly translational efficacy data on both tumour regression and metastasis within 5 days. By enabling access to functional in-vivo data in only 5 days, these zebrafish models are helping to increase the speed of pre-clinical development and success rate of cancer drug candidates.
The aforementioned embryos are used to generate zebrafish patient tumour-derived xenograft (ZTX) models that can be utilised across a wide range of oncology drug development functions, including for:
- Screening various drugs or drug concentrations in multiple CDX/PDX-models
- Screening multiple CDX or PDX models to find the right indication for your drug
- Finding the best combination treatment for your compound
- Reconstituting patient specific tumour micro-environments with immune and stromal cells - Finding the right PDX model for your mouse PDX study
To generate these models, human tumour cells are implanted into the zebrafish embryos, which go on to form a solid microtumour with vascular engagement and metastases after just three days. The tumour cells used in implantation can be cultured using a variety of different techniques, including cell-lines, PDX-models or even primary tumour cells. The models can then be used to test all different types of pharmaceutical compounds, including small molecules, large molecules, antibodies, ADCs, nanoparticles and more.
The ZTX™ ONCOLEADS platform has been validated against 50 mouse PDX models, with a high similarity observed between responses in mice and responses in the ZTX system. The platform has also been used in clinical collaborations, where responses to standard treatments were tested in patient primary tumours using the ZTX platform, and then compared to real-life patient responses. These studies have shown that there is a very high correlation between the results from the ZTX platform and true clinical outcomes in patients. With solid data supporting the translation of results from the ZTX system to both mice and humans, there is high certainty in the claim that the ZTX platform is a reliable and translational in-vivo model for the preclinical testing of new oncology therapies.
In addition, the zebrafish system has been proved to be a valuable tool in immuno-oncology research. The ZTX platform works as an in-vivo platform to test T cell- mediated immunotherapy. The ability of the platform to host human immune cells without any alterations makes it a powerful tool for exploring any immune-oncology research you want to validate.
Benefits of using zebrafish embryos
The platform utilises zebrafish at embryonic and larval stages, which provide a number of significant advantages, such as:
No ethical permissions required: at these stages, zebrafish embryos are not considered a research animal and so no ethical permissions are needed for the work. This greatly facilitates working with new drugs that have unknown effects on animals and humans.
Embryo transparency: at this development stage, zebrafish embryos are transparent, enabling clear visualisation of the growing human fluorescent-dyed cancer cells.
Absence of immune system: zebrafish embryos lack an immune system, enabling human cells to grow within the embryo without risk of rejection.
High-throughput screening options: the zebrafish platform carries high-throughput screening in a 96-well plate, which allows for high throughput screening with 20 embryos in each group.
Require minimal quantities of test substances: for example, a total of 2ug of substance is required to test 100 embryos in a 200ug/kg concentration.
3. Is the ZTX™ ONCOLEADS zebrafish platform right for my preclinical study?
It is a challenge to select the optimal treatment for individual cancer patients. 12 million new cancer cases are being diagnosed every year, and the majority of these require medical treatment, therefore we need better methods that can predict individual responses to different types of therapy.
The use-cases for the ZTX™ ONCOLEADS platform are extensive, ranging from supporting the process of preclinical mouse model selection to enabling rapid drug screening for novel cancer treatments. The platform also provides a cutting-edge solution for precision medicine in oncology by allowing investigation of how efficiently different treatments can inhibit tumour growth and metastasis in a specific patient-tumour micro-environment. Considering part of the reason why treatments fail is that only a minority of patients show a response, this type of investigative approach is important to be able to separate responders from non-responders early in the drug development process. Establishing this separation is key, because with more than 200 different cancer drugs on the market and a multitude of other treatment options available (e.g. surgery, radiation therapy, etc.), patients that do not respond to current 1st line treatments may likely benefit from an alternative drug or procedure, while patients that do show a response tend to have an excellent survival rate.
Finally, it is worth noting that the significant time and costs savings that this platform enables make it a highly attractive option for projects that are on a shorter schedule or tighter budget. With the time taken for in-vivo data collection reduced by approximately 94% and costs cut by a further 90%, this option offers significant savings that could help improve the feasibility of your next preclinical study.
Want to learn more about the ZTX™ ONCOLEADS platform, as well as other models in our inventory? Search our Cancer Models Platform or contact us today.