PDX Mouse Models are Reliable Stand-Ins for Human Tumors

Using mouse models has been a vital tool for cancer researchers to study human tumours for a long time. Even though the PDX models are not replicas of human diseases, they are still considered reliable stand-ins. The international medical community has come together to discover how close the mouse models can mimic cancer conditions in humans, creating the PDX mouse model. PDX models for cancer are constantly being improved to be more accurate in studying human tumours.

What are PDX models?

PDX is short for patient-derived xenograft. This means that the tumour cells are taken from a human patient and then grafted onto a mouse. The tumour cells1 will then grow in the mouse, creating a tumour similar to the human tumour.

According to the January 7 report in Nature Genetics2, there have been significant changes in mouse tumour genes related to cancer.

Why are Mice Good Model Organisms?

Any other research method – like tumour cells in a petri dish – won’t be as biologically relevant as testing on animal models. But why mice?

Take any other model organism – and mice would still be better. The mice genome is 99% similar to the human genome, the researchers already have the tools to experiment with mice genes, and the small size of a mouse makes it cost-efficient to use them in multiples for thorough research.

Cancer cells in an animal body are essentially growing tissue. As a result, the tumour interacts with the other cells and tissues – like in a human. There is more than one mouse model used for tumour research. In one of them, mice have grown artificially in labs and then injected with cancer cells for research. This inexpensive way to rapidly produce a large number of mice – is called ”cell lines”.

However, these are lab-grown mice, but our humans are very much natural. Jeffrey Moscow, M.D., of the Cancer Therapy Evaluation Program in NCI’s Division of Cancer Treatment3 and Diagnosis, said that lab-grown mice tend to go through genomic changes, which don’t make them a proper representative of how the tumour would react in a human body.

Are PDX Models Accurate?

The efficacy of using PDX models depends on the biomedical differences and similarities that evolve between humans and mice. Dr Jeffrey Chuang, PhD of the Jackson Laboratory for Genomic Medicine, has said that we need an up-to-date and holistic study to ascertain the validity of PDX models in aiding human cancer research.

This is extremely important because the researchers can only move on to human clinical trials because of the safety issues and significant investment involved.

To date, the most recent study has shown variations in the characteristics of human tumours and tumours in PDX mice – as said by a cancer researcher independent from the study – Senthil Muthuswamy4, PhD, of Beth Israel Deaconess Medical Center and Harvard Medical School. In addition, compared to the cell lines model, the PDX model takes longer for conclusive results – about six months to one year.

However, this study has still proven useful, even if they don’t establish the accuracy of the PDX model. PDX models are crucial in testing the efficacy of experimental drugs and drug combinations.

Cancer Research with PDX Models

The PDX model is here to take over the shortcomings of the previous mouse models. The mice used in the PDX models don’t have an immune system, so the human tumour cells implanted in them won’t be attacked by their immune cells. This process is called ‘engrafting.’

Once the tumour in the mice is fully grown, tumour fragments are taken and implanted into other mice. This process is repeated when the second line of mice have their tumours fully grown – and is known as ‘passaging.’

The Relevance of PDX Models Today

The PDX model has been questioned about being inaccurate because, after multiple rounds of passaging through natural mice, genomic changes peculiar to mice might have occurred. However, such changes aren’t similar to a human body’s genomic response.

A 2017 study by the Harvard and Massachusetts Institute of Technology5 (MIT) confirmed that there had been multiple genomic changes in the mice within the first few rounds of ‘passaging’ – genomic changes very different from that in a human. Furthermore, these genomic changes in the mice affected their reaction to cancer medication and therapy. However, other small studies have drawn an opposite conclusion – with substantial similarities between human tumours and that in PDX mice.

An Analysis of PDX Models

To conclude, a new study was required. So PDXNet and EurOPDX joined to test 500 PDX models with 300 matching human samples – 16 cancer types and tumours from Asia, Europe, and North America.

The RNA testing method in the MIT testing is used, along with an additional DNA testing round with whole-exome and whole-genome sequencing to improve accuracy. The results were that there were no multiple copies of genomic transitions in the PDX mice – especially the mice which have been engrafted way later than the first line of PDX mice.

The genomic changes were similar to the human samples with metastatic colorectal and breast cancer. This is a victory for PDX models.

The Humanized Mouse PDX Model

We are yet to look into the next testing phase involving tumour cell variations among human patients. The next phase of PDX models will have immune cells in the mice. In addition, human stem cells will be engrafted in the mice to simulate the immune system reaction of a cancer patient to new drugs. There are three types of humanized mice:

  1. PDX mice engrafted with human genes (Transgenic mice)
  2. Humanized mice carry an organ of the cancer patient, like a hepatocyte infusion.
  3. The PDX mice without immune cells derive an immune system from the human stem cells engrafted in them.

Challenges Involved in PDX Models

  1. The PDX model testing results after a long tumour latency period of 4 months to one year.
  2. The time involved and the accuracy of PDX models differ across the types of cancers and hosts. For example, PDX models are easy to formulate in cancer types other than breast cancer.
  1. PDX models are costly to operate and require specific lab equipment.
  2. PDX models have difficulty reaching metastasis since it involves two methods – grafting the tumour directly in the mice or injecting tumour cells. Each method has its pros and cons.
  3. PDX models are ineffective for early-stage cancers; since then, the immune system has been weak and doesn’t show any resistance to the cancer cells.
  4. Genetic diversion is inevitable. Todd Glub, Head of the Cancer Program Broad Institute, found that 12% of genomic changes had already occurred by the fourth round of passage.

These limitations can be overcome by introducing a fresh batch of humanized mice or orthotopic cancer models in the PDX 6model testing.

Key Takeaways

The PDX model has been beneficial for drug evaluation and tumour screening. The five common types of cancer – lung, breast, colorectal, gastric, and prostrate – have been accurately detected in origin and growth with the PDX model.

Despite limitations, it is said to be one of the most standard and reliable testing methods. As a result, PDX model applications in personalized medicine, co-clinical trials, immunotherapy, cancer drug screening, and biology have been quite significant. This may be why many countries look forward to developing PDX biobanks, libraries, and pharmaceutical companies to harness this resource.

  1. Boumahdi, Soufiane, and Frederic J. de Sauvage. “The great escape: tumour cell plasticity in resistance to targeted therapy.” Nature reviews Drug discovery 19.1 (2020): 39-56. ↩︎
  2. Claussnitzer, Melina, et al. “A brief history of human disease genetics.” Nature 577.7789 (2020): 179-189. ↩︎
  3. Geiger, Ann M., et al. “Evolution of cancer care delivery research in the NCI Community Oncology Research Program.” JNCI: Journal of the National Cancer Institute 112.6 (2020): 557-561. ↩︎
  4. Koikawa, Kazuhiro, et al. “Targeting Pin1 renders pancreatic cancer eradicable by synergizing with immunochemotherapy.” Cell 184.18 (2021): 4753-4771. ↩︎
  5. Mallapaty, Smriti. “How China could be carbon neutral by mid-century.” Nature 586.7830 (2020): 482-483. ↩︎
  6. Abdolahi, Shahrokh, et al. “Patient-derived xenograft (PDX) models, applications and challenges in cancer research.” Journal of Translational Medicine 20.1 (2022): 206. ↩︎

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Icy Health Editorial Team

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