Prostate cancer is one of the most common cancers. As many as 1 in 8 men will get prostate cancer. Fortunately, it is not always life-threatening. If caught early, there is a chance that it has not progressed to a metastatic stage and can be cured.
Decades of research have provided the medical community with effective therapeutic options. Today, localized primary prostate cancer has a five-year survival rate of nearly 100%. So why is the investigation still ongoing?
The research landscape for prostate cancer
While many prostate cancers grow slowly, are confined to the prostate gland where they don’t necessarily cause serious damage, and require minimal treatment, some types of prostate cancer spread quickly and become resistant to hormonal therapies.
A fraction of men who get prostate cancer relapse after a few years, but because the incidence of the disease is important, those numbers are relatively large. In the UK, a man dies from prostate cancer every 45 minutes, equating to around 12,000 individuals a year, and most of them will have had metastatic or drug-resistant forms of the disease.
“More research and funding is needed not only to create better cures, particularly for patients with drug-resistant forms of the disease, but also to find ways to improve patients’ quality of life. To do that, we need to focus on prevention and a better understanding of the disease – and animal research is crucial for that last part”, explains Dr. Marco Bezzi, who leads Tumor Functional Heterogeneity at the Institute of Cancer Research.
Research focused on drug-resistant prostate cancer
About 70 years ago, researchers showed with animal research that prostate tumors are very dependent on the androgen receptor pathway in the early stages. The work in animals helped to determine how the cancer cells respond to hormones, leading to the development of the first hormonal treatments. Depriving the cells of androgens – testosterone in men – became the main treatment for patients.
Unfortunately, while this type of treatment is highly effective against most types of prostate cancer, some appear to be resistant. The tumors reactivate the androgen-sensitive pathway.
In recent years, research has largely focused on understanding how the tumors escape hormonal therapy, change and evolve over time. Scientists have also been looking for better inhibitors of the pathways and other viable solutions to treat these drug-resistant forms of prostate cancer that are no longer susceptible to hormonal castration.
Different mouse models tell different parts of the story
Animals were and still play an important role in the discoveries. Mice and humans are clearly different, but as models of the disease, the rodents are a fundamental part of the puzzle. Each mouse model contributes a crucial piece, a glimpse of the bigger picture.
Ideally, a mouse model would mimic every step of the disease and respond the same way humans do to each therapy, but that’s not the case. Researchers are using a number of mouse species to tell different parts of the story.
Doctor Bezzi explains: “In the best of the world, the ideal mouse model would initially be sensitive to hormone therapy or castration, but then develop resistance and metastases. This would enable the study of basic biology, the understanding of the mechanisms behind disease progression and the testing of new drugs. We try to think about the whole picture when creating a mouse model of the disease.”
A large number of mouse models are available to researchers studying prostate cancer. From xenograft models, immunodeficient mice implanted with human cancer cells, to genetically modified animals with inactivated tumor suppressor genes.
Each model has its advantages and disadvantages. Some will tend to model the earlier, hormone-dependent stages of the disease, while others will model the resistant stages with tumors migrating to different parts of the body, including the bones.
The limits of modeling metastasis
Unfortunately, the metastatic process is extremely difficult to reproduce in animal models.
“The whole field is aware of this shortcoming and invests a lot of effort to gradually develop better models of metastasis from a translational point of view,explains Dr. Bezzi.
Metastatic disease is genetically very complex. Genetic sequencing of tumors in patients has shown that metastatic cells contain a diverse range of genetic abnormalities. The first mouse models were developed in which one gene was missing at a time. These were reasonably good at modeling the initial stages of prostate cancer, but the genetic background was probably not aberrant enough to modulate the later, more aggressive stages.
In efforts to increase the genetic complexity of these mouse models, researchers began crossing these single aberration lines to get mice with two different aberrations together, which developed more aggressive prostate cancer. More recent models now have up to three combined genetic abnormalities and show even more metastatic growth. Genetic tools have improved tremendously in recent years, meaning it’s possible to manipulate the genetics of these cells with a resolution that wasn’t possible even a few years ago. The hope is high that this will translate into groundbreaking work.
However, it can take years for patients to have their cancer escalate to the metastatic stages, and the mouse lifespan just isn’t that long. To incorporate that time dimension, researchers are also using xenograft models where the human tumor lines are injected into mice and developed from one mouse to another. This serial recipient model gives the tumor more time to develop into something more aggressive.
“We still don’t have the perfect model”, says Dr. Bezzi. “And we may never get that perfect model. We are starting to realize that every cancer differs from patient to patient. However, we can try to refine our models as best we can with new technology and support better use of animals, in parallel with the development of in-lab, in-vitro systems.”
Learn more about animal models of prostate cancer: https://www.animalresearch.info/en/medical-advances/diseases-research/prostate-cancer/
Last modified: November 24, 2022 10:20 AM