·
2 minute read
Cancer research is constantly evolving, seeking new methods to better understand and treat this complex disease. Among the most groundbreaking developments in this field are patient-derived xenograft (PDX) models. These models have revolutionized our approach to studying tumors by preserving the heterogeneity and molecular characteristics of a patient's tumor. This blog post aims to provide an in-depth look at the heterogeneity of PDX models and why it’s important to have diversity in your preclinical in vivo studies.
The Importance of PDX Models
Unlike traditional cell line-based models, PDX models retain the genetic diversity and molecular complexity of the original tumor. PDX models offer researchers a closer approximation of how human tumors behave in vivo, with different cell populations responding differently to therapies. They provide a dynamic and clinically relevant platform for studying tumor growth, metastasis, and response to treatment, making them a powerful tool in the fight against cancer. (Read our blog "The Ultimate Guide to Designing a Mouse Clinical Trial and Data Analysis")
Models pretreated with targeted therapies are ideal to test next-generation agents. For example, when developing a drug that aims to overcome resistance to the standard of care therapy in a given tumor type, choosing models pretreated with that standard of care agent for our efficacy study will reveal true therapeutic effects in the target patient population. (Read our blog "Accelerating Innovation & Drug Development with Pre-treated PDX Models")
Tumor Heterogeneity of PDX models is important for translational oncology studies
One of the most significant advantages of PDX models is their ability to preserve tumor heterogeneity. Tumors are not uniform; they consist of various cell types with different genetic mutations and behaviors. On the contrary, traditional cell lines are developed in vitro by clonal selection, leading to a less accurate representation of the human disease.[1]
PDX models also retain the molecular characteristics of the original tumor. This includes genetic mutations, epigenetic modifications, and gene expression patterns. By maintaining these features, PDX models provide a more accurate representation of the human tumor genetic background, which is crucial for developing effective therapies.[1]
Advancing Cancer Research with PDX Models
The ability of PDX models to preserve tumor heterogeneity and molecular characteristics has significantly advanced cancer research. Researchers can study the behavior of different tumor subpopulations, identify potential targets for therapy, and evaluate the efficacy of new treatments in a more realistic setting.
PDX models have heterogeneous biomarker expression. The figure below, for example, shows the expression of KRAS in Champions’ PDX models varying across and within tumor types. Selecting PDX models with a higher KRAS expression will be paramount to successfully test KRAS inhibitors and could provide more clinically relevant results.
Nonetheless, a PDX model with elevated KRAS expression will still present with heterogeneous expression across the different cell clones within the tumor, a setting that realistically reproduces the human tumor heterogeneous cell composition. In this setting, a KRAS inhibitor might only be partially effective at killing the tumor because cell clones with lower KRAS expression within the tumor might not be affected, resulting in lower overall therapeutic efficacy. Similarly, in the clinic, we could observe a partial response followed by tumor progression, due to the selection of the low KRAS-expressing cell clone within the tumor. For this reason, studies that use PDX models instead of cell line-derived models will produce more reliable and clinically relevant results.
KRAS gene expression across Champions' PDX models of different tumor types.
Patient-derived xenograft models have revolutionized cancer research by providing a more accurate representation of human tumors. Their ability to preserve tumor heterogeneity and molecular characteristics makes them an invaluable tool for studying cancer biology, testing new therapies, and personalizing treatment plans. By continuing to develop and refine these PDX models, researchers can accelerate the discovery of new treatments and bring them to patients faster.
Champions Oncology has over 1500 clinically relevant PDX models that can accelerate your oncology research program. Our models have broad clinical annotation and have been deeply characterized using NGS (WES & RNA-seq), proteomic, and phospho-proteomic datasets to interrogate the heterogeneity of the tumor. To learn more about our PDX tumor models, access Lumin Analytics.
