Over the year’s cancer research and drug development have moved from developing “simple” chemotherapies which stop tumors proliferating, onto the innovative field of precision medicine, based on the genetic changes and make up of individual patient tumors.
Targeted agents across a wide range of gene mutations and fusions have been approved or are in development. However, their use usually results in acquired resistance, often due to further mutations arising. For example, gastrointestinal stromal tumors show sensitivity to imatinib, based on primary KIT mutations. Treatment with imatinib though, causes rapid acquired resistance, with a range of secondary mutations occurring within patients. This means that a new agent (or range of agents) is required to overcome the new resistance genotype.
Drawbacks to Developing New Targeted Agents – A Lack of Early Stage Cell Lines and Models
One major challenge when developing new targeted agents is preclinically replicating the resistance genotypes and wide range of mutation patterns seen in the clinical population. For a full drug development program, cell lines, early stage conventional xenografts, and patient-derived xenografts (PDX) featuring your mutation(s) of choice would be useful.
As PDX closely recapitulate patient disease, a large collection should hopefully contain some models meeting specific needs for late stage in vivo study. But there is often a lack of a corresponding early stage in vitro cell culture system – immortalized cell lines and their related xenograft models don’t always offer the same wide range of genotypes, or can have drifted sufficiently from original disease to not be particularly useful.
PDX-Derived Resources for Early Stage Drug Discovery
One way to overcome this problem, and to have an integrated drug development program, is to back translate PDX to in vitro and early stage in vivo resources. Cell lines can be derived from PDX maintaining essential histopathological features and genetic profiles of the original patient tumors, meaning that any rare fusion or mutation you were targeting in the PDX will still be present for cell screening. This also includes features such as biochemical signaling and responses to tumor cell autonomously targeted therapeutics.
These cell lines are derived from mouse stromal cell-depleted cancer cell cultures from PDX tumors, and usually kept at early passage (<10) to prevent any drifting from original disease. They can be used for high throughput screening and a fast turnaround for assessing targeted drug efficacy prior to in vivo study. Cell lines such as these are also amenable to 3D culture, more closely representing tumor biology in situ.
In vivo studies follow, such as compound screening and PK/PD analysis, where traditional cell line derived xenografts would normally be used. The PDX-derived cell lines can be established as "conventional" xenograft models, again providing the genetic feature of interest in a robust system for early stage drug discovery.
Integrated Platform of Cell Lines and Xenograft Models
When an agent is closer to clinical study, and more predictive data is needed, the original PDX model can be re-employed, providing key data informing on patient response to guide trial design.
This complementary panel of cell lines and xenograft platforms come together to form a critical, often missing link, between in vitro testing and predicted clinical efficacy in drug development.
