Research Update Corner
By Mila McCurrach
Fall 2013: On the Road to New Pancreatic Cancer Clinical Trials
Before testing a new cancer therapy in people, a great number of studies need to be done to make sure that it is safe and has high potential of being effective. Many of these studies are done in animal models, which have been instrumental in bringing chemotherapies to patients and saving human life. The earliest animal systems were developed more than 30 years ago and include invertebrates, fish and mammals. Pancreatic cancer researchers, many funded by the Lustgarten Foundation, have developed several types of models that are moving us closer every day to a cure. While there is no clear-cut measurement to determine just how far we are from discovering a pancreatic cancer cure, discussing the evolution of the model system, as well as the pros and cons of each model, can help paint a broader picture of the amazing leaps and bounds that have already been made and the ones that lay on a hopeful horizon.
Believe it or not, fish not only have a pancreas but can also develop pancreatic cancer naturally. Zebrafish are relatively easy and inexpensive for scientists to study, as thousands can be bred per day in a single tank. Their bodies are also transparent, so you can literally see the tumors as they grow. Zebrafish are used to study the genes that cause the growth and spread of tumors, as well as new drug therapies that may be effective against them. Despite the advantages of the Zebrafish model,, there are clearly many differences between fish and mammals, which limit the insight into the human element of the disease.
Mice are another system that can be used to study pancreatic cancer and potential treatments. Since they are mammals, they share more similarities with humans than zebrafish do. There are several types of mouse models with different strengths. One model, called a xenograft, uses human tumors transplanted under the skin of mice. The advantage of this model is that it allows us to study a human tumor in a living organism. The disadvantage is that only very aggressive and advanced pancreatic tumors will grow this way, so scientists aren't able to study the early stages or progression of the disease. In addition, as pancreatic cancer does not normally grow under the skin, its surroundings are dramatically different and may affect how the tumor responds to therapy. A second model, called Genetically Engineered Mouse Models or GEMMs, involves mice that have been genetically altered to naturally develop pancreatic cancer during their lifespan. These pancreatic cancers develop, progress and look almost identical to pancreatic cancers in humans. The advantage of this system is that scientists get to observe every stage of the disease in a natural setting. These animals have been critical in helping define new early detection approaches, as well as new therapeutic options. The disadvantage is that regardless of how similar these cancers are, they are still mouse tumors and not patients, which poses limitations.
Personalized Mouse Model
In order to address some of the issues with the mouse models described above, researchers have more recently developed animal models that can grow human pancreatic cancers in the pancreas of mice. Referred to as personalized models, scientists inject pieces of a patient's tumor into the specially designed mice. These mice can be used to test a cocktail of cancer drugs to pinpoint which one(s) may work best before therapy even begins. This revolutionary model system brings scientist one step closer to receiving human-like drug testing results without actually having to test several drugs on a human patient.
While personalized mice models seem promising, there are also some challenges facing the method. For instance, it is very difficult to set up a model of this caliber, since all aspects must be in place in the beginning stages of the patient's disease in order to be effective. Additionally, this system is very expensive, and it is a long process from the initial set up to the observation stage.
In the past year, a groundbreaking new model has been developed in the Lustgarten Pancreatic Cancer Laboratory directed by David Tuveson. This model does not use a living organism but instead grows human cells in pancreas-like spheres in an incubator. These are referred to as organoids. The organoid model involves taking human tumor cells from patients immediately after surgery and growing them in a specially coated plastic dish in the laboratory. These cells grow into a mini tumor and are then surrounded by other normal pancreas cells, giving the organoids an environment similar to a human pancreas. Since many cells can be grown quickly, it is believed that one day we may be able to help test many different drug reactions within days or even hours. While this technology is still in its infant stage, there are hopes that it may help reduce the number f studies needed in animals before a drug is brought to clinic.
Clearly, model systems for studying pancreatic cancer and possible treatments have greatly evolve over time and continue to grow more sophisticated with each passing day.