A Patient Derived Xenograft (PDX) model is an animal model established by directly implanting fresh tumor tissue fragments or single cells from a human patient's tumor into immune-deficient mice. This allows the implanted human tumors to continue growing and spreading in the mice, thereby recapitulating human cancers. PDX models maintain the essential characteristics and heterogeneity of the original patient tumors and closely mimic the mechanisms, biological behavior and response to therapy of the patient's cancer. Advantages of Patient Derived Xenograft Model over Cell Line Models While cell line models have been widely used in cancer research, they have certain limitations like genetic drift over time in culture and loss of tumor heterogeneity. Patient Derived Xenograft Model models overcome these limitations and retain the genomic, histological and molecular characteristics of the original patient tumors. They recapitulate the epithelial-to-mesenchymal transition, tumor microenvironment interactions and develop resistance to therapy similarly to patients. PDX models are also more predictive of drug responses in patients compared to cell line models. This makes PDX models a clinically relevant pre-clinical platform that bridges the gap between cell line research and human clinical trials. Maintaining Tumor Heterogeneity One of the major advantages of PDX models is their ability to maintain intratumoral heterogeneity from the patient’s tumor. Cancer is known to be a heterogeneous disease with various subpopulations of cancer cells with different genomic profiles co-existing within the same tumor. PDX models retain this heterogeneity on serial passaging and transplantation into mice over several generations. Studies have shown PDX models preserve the complex cellular diversity as well as variability in gene expression and mutational profiles of the original patient tumors. This heterogeneous tumor growth closely mimics human cancer progression. Modeling Tumor Microenvironment The tumor microenvironment, comprising various types of immune cells, fibroblasts, blood vessels etc. plays a critical role in cancer growth and treatment response. Unlike cell line models, PDX models maintain not only the cancer cells but also the non-neoplastic human stromal cells from the original patient tumor. This humanized stroma in PDX engrafted mice supports vascularization and emergence of supportive fibroblasts and immune cells. Presence of the human tumor microenvironment makes PDX models more predictive of clinical outcomes, especially for immunotherapies. Several studies have demonstrated PDX models can recapitulate critical aspects of tumor-immune interactions and response to immune checkpoint therapies. Predicting Drug Response A major application of PDX models is preclinical testing of novel anti-cancer drugs to predict clinical response and develop better personalized treatment strategies. Several studies have shown PDX models can accurately predict patient responses to FDA-approved and investigational anticancer therapies, including targeted therapies and chemotherapy. In one study, lung cancer PDX models achieved 81% accuracy in predicting patients’ response to erlotinib. Another study showed 88% accuracy of colorectal cancer PDX models in forecasting clinical responses to five different regimens. Such predictive value makes PDX models more clinically relevant than cell line based studies for personalized medicine and precision oncology applications. PDX models are also being used to study mechanisms of drug resistance and identify biomarkers for sensitivity/resistance. Modeling Metastasis Metastatic spread to distant organs is responsible for majority of cancer-related deaths. While traditional models inadequately mimic metastasis, PDX models successfully engraft primary as well as metastatic lesions from different cancer types and their associated metastatic patterns. Implantation of breast, prostate and pancreatic cancer PDX models has recapitulated organ specific metastasis to lungs, bone and liver respectively. These metastatic PDX models enable studying factors regulating metastatic colonization and evolution along with evaluating anti-metastatic therapies. Researchers are further developing metastatic cascade and real-time imaging models using PDX models to better understand metastasis dynamics. Applications in Personalized Medicine By closely representing individual patient tumors, PDX models hold immense potential for personalized cancer treatment. PDX models can be established from biopsies of refractory or recurrent cancers to help identify effective second and third line therapies. Several cancer centers worldwide have biobanks of PDX models representing varying tumor types, stages, mutations to aid precision treatment decisions. PDX based avatar mouse models are also being developed where a patient’s disease can be tracked in real-time and different therapies tested pre-emptively.
In Summary, integration of PDX platforms with comprehensive genomic and immune profiling will optimize treatment selection and monitoring for each cancer patient. Overall, PDX models are revolutionizing cancer research by enabling a highly predictive and personalized approach towards evaluating and developing new anti-cancer strategies.
