PDX models are created by implanting actual tumor tissue from a patient directly into an immunocompromised mouse. This process generates a living system that closely mirrors the original patient’s disease. PDX models offer a more biologically relevant platform than traditional laboratory methods for studying human cancer. This ability to grow and study a patient’s own tumor outside the body is changing how researchers approach drug discovery and therapeutic decision-making.
How PDX Models are Established
Creating a PDX model begins with obtaining fresh tumor tissue, usually through surgery or a biopsy. The tissue is quickly fragmented into small pieces and implanted into a highly immunocompromised mouse, which prevents the rejection of the human tissue.
The fragments are often implanted subcutaneously for easy monitoring. Researchers may also use orthotopic implantation, placing the tumor into the mouse organ corresponding to the tumor’s origin. Orthotopic placement better mimics the original tumor’s environment, but it is technically more challenging.
Once the tumor grows in the first mouse (the F0 generation), a portion can be harvested and transferred, or “passaged,” into successive generations. This serial passaging expands the tumor volume for large-scale experiments. It creates a renewable tissue resource that retains the characteristics of the patient’s original cancer.
The Predictive Power of PDX
The advantage of PDX models is their fidelity to the original human tumor. Since the tumor is not subjected to the artificial selection pressures of cell culture, it maintains the patient’s specific genetic and molecular features. PDX models preserve the tumor’s architectural complexity and histology, remaining consistent with the patient’s disease.
These models maintain the tumor’s heterogeneity, which is the presence of different subpopulations of cancer cells. This cellular diversity is a major factor in treatment resistance, and capturing this complexity helps predict drug response. Furthermore, the models largely retain the tumor microenvironment, including the human-derived stromal components.
Although mouse stroma and blood vessels gradually replace the human stromal cells, the tumor cells themselves remain human. This preservation of the tumor’s unique biological context makes PDX models highly predictive of clinical behavior. The models reproduce clinical outcomes observed in corresponding patients, validating their utility for testing new therapies.
Driving Personalized Treatment
PDX models are changing precision medicine by offering a platform to test treatment strategies tailored to an individual’s cancer. This approach, called “avatar” modeling, involves screening a wide range of anti-cancer drugs on the living PDX model. Researchers can determine which therapies are most effective against that patient’s unique disease profile before treatment begins.
This patient-specific testing identifies optimal treatment regimens and helps predict drug resistance. This process is used in co-clinical trials, where drug studies in PDX models run parallel to human clinical trials. This accelerates the integration of research findings into patient care.
PDX models are also widely used in preclinical drug development to validate new drug targets and screen novel compounds. They help researchers understand the mechanisms of drug action and resistance across diverse tumor panels. Using models established from pre-treated tumors is effective for studying how cancers adapt to evade therapy.
The Current Challenges of Using PDX Models
The widespread adoption of PDX models is limited by several practical and biological challenges. Logistically, the models are costly and require a lengthy turnaround time, often taking several months for engraftment and tumor growth. This time requirement may be too long to influence initial therapy decisions for patients with aggressive cancers.
A biological constraint is the immunodeficient nature of the host mouse, which is necessary to prevent tissue rejection. This lack of a functional human immune system makes PDX models unsuitable for studying immunotherapies, which rely on a robust immune response.
Altered Microenvironment and Drift
While the models retain human tumor cells, the surrounding stroma, blood vessels, and immune components are quickly replaced by mouse cells. This replacement alters the tumor microenvironment, potentially influencing tumor behavior and drug response compared to the patient’s original tumor. There is also a risk of genetic drift, where the tumor may evolve slightly over successive passaging. These factors contribute to variable engraftment rates, complicating the timely use of the models.