A patient derived xenograft (PDX) is a specialized research model where a patient’s tumor tissue is implanted into an immunocompromised animal, typically a mouse. This process, a form of xenotransplantation, creates a living model of an individual patient’s cancer outside their body. The primary goal is to maintain the original tumor’s characteristics within the mouse, allowing researchers to study its behavior and potential responses to treatments.
Creating a Patient Derived Xenograft Model
The creation of a patient derived xenograft model begins with acquiring tumor tissue from a cancer patient, typically from a biopsy or surgical resection. Once collected, the tumor is processed into fragments or single-cell suspensions, then implanted into an immunocompromised mouse.
Immunocompromised mice are used because their suppressed immune systems prevent them from rejecting the human tumor tissue. Implantation can occur subcutaneously, under the skin, or orthotopically, meaning into the same organ as the original tumor. After implantation, mice are monitored for tumor growth, which can take several months to establish.
Once the tumor has successfully grown in the initial mouse, it can be harvested, divided, and reimplanted into additional immunocompromised mice. This process, known as “passaging,” allows for the expansion of the tumor model into a larger cohort, providing a renewable resource for research. Subsequent generations of the model are designated as F1, F2, F3, and so on.
Applications in Personalized Cancer Treatment
Patient derived xenograft models serve as a surrogate for an individual patient’s tumor, providing a platform for personalized cancer treatment. Researchers can test different cancer drugs and treatment combinations directly on these mouse models to determine which therapies are most effective against that specific patient’s cancer. This enables a more tailored approach to therapy and can help identify drug resistance before a treatment is given to the patient.
PDX models are also valuable for broader cancer research, aiding in the discovery and validation of new therapeutic agents. They allow for the evaluation of novel anti-cancer compounds and combinations, assessing their efficacy. Researchers can use these models to identify biomarkers, molecular indicators that can predict how a tumor might respond to a particular therapy. These insights guide drug development and patient stratification.
Beyond individual patient applications, PDX models are utilized in co-clinical trials, where preclinical studies in mice run in parallel with human clinical trials. This strategy helps refine treatment protocols based on findings from both the mouse models and human patients. This integrated approach helps bridge the gap between laboratory research and clinical outcomes, accelerating the development of more effective cancer therapies. The high fidelity of PDX models to the original tumor’s genetic and histological features makes them useful for predicting clinical efficacy.
How PDX Models Differ from Traditional Research
Patient derived xenograft models offer distinct advantages over older, more conventional cancer research methods, particularly established cancer cell lines and cell-line derived xenografts (CDX). Traditional cancer cell lines are grown in laboratory dishes, or in vitro, for extended periods. During this prolonged culture, these cells can undergo significant genetic and phenotypic changes, making them less representative of the original patient’s tumor.
Cell-line derived xenografts (CDX) are created by implanting these established cell lines into immunocompromised mice. While useful for high-throughput drug screening due to their simplicity and reproducibility, CDX models often lack the complex heterogeneity and intricate architecture found in actual human tumors. The adaptation of cell lines to in vitro culture conditions can also result in a loss of cellular diversity and alter their biological characteristics.
The primary advantage of a PDX model is its ability to better preserve the original tumor’s biological characteristics. Because patient tumor tissue is directly implanted into the mouse without intermediate cell culture steps, PDX models maintain the complex structure, cellular diversity, and genetic makeup of the primary tumor more accurately. This preservation of the tumor microenvironment, including interactions between cancer cells and surrounding stromal cells, offers a more realistic representation of human cancer biology compared to models derived from cell lines.
Key Considerations and Limitations
Despite their advantages, patient derived xenograft models have specific considerations and limitations. Establishing a functional PDX model can take several months, a timeline that may not be feasible for patients who require immediate treatment. The overall cost associated with developing and maintaining PDX models is also substantial.
Another challenge is that not all patient tumors successfully grow, or “engraft,” in the mouse host. Engraftment rates can vary widely depending on factors such as tumor type, the proportion of cancer cells in the sample, and the implantation technique. This variability means that not every patient’s tumor can be successfully modeled using this method. Freshness of the tissue and adequate sample size also influence engraftment success.
A scientific limitation of current PDX models is the absence of a fully functional human immune system in the mouse host. While immunocompromised mice are necessary to prevent rejection, this lack of an intact human immune system means that PDX models are less suitable for studying immunotherapies, which rely on immune cell interactions. Over time, the human stromal cells (support cells) surrounding the tumor can also be gradually replaced by mouse stroma, potentially altering tumor behavior and drug response.