Bruno Doiron, PhD, Biomedical Researcher, Department of Medicine at UT Health San Antonio, talks about using mice to test new treatments for pancreatic cancer.
Interview conducted by Ivanhoe Broadcast News in May 2018.
It takes a while to get to market. Are you in the research phase at this point?
Dr. Doiron: Yes, I am. It is very important to understand that to bring a new medicine to humans, you need a good animal model. We do need an effective animal model to bring a successful treatment of pancreatic cancer to humans. If you do not have an efficient animal model to begin with, you can fool yourself because your model simply would not mimic what happens in humans. Therefore, you might cure an inadequate mice model, meaning the disease developed there is completely different from what’s happening in humans in reality. Pancreatic cancer has remained refractory to treatment. In large part, these results are due to the lack of an animal model that mimics pancreatic cancer in a human being. So, this is the reason why this new model we developed in my laboratory is so essential here.
Moreover, while you were sitting around, how did this idea come to your mind?
Dr. Doiron: People usually like the idea of a Eureka moment, but the Eureka moment or sudden flash comes only to a prepared mind. I agree with Louis Pasteur’s statement, “Chance favors only the prepared mind.” Indeed, I have years of research experience and dedication which prepared my mind for this moment. I checked the scientific literature on pancreatic cancer models and realized that the existing ones poorly mimic the development of cancer in a human being. Therefore, my idea of creating a new human pancreatic cancer model makes much sense. There is a long way to go before reaching a Eureka moment. When it happens, you think, “Yes, this idea needs to be tested; it is worth it.”
When did it finally germinate? There had to be a Eureka moment when you put everything together from the stewing in your mind. When that happened what did you think to yourself?
Dr. Doiron: In fact, I was able to put all the puzzle pieces together, to connect the dots. Importantly you need to take off noisy data from the scientific literature. Select only the relevant scientific data. When I finish connecting the dots, I check the scientific literature to validate my idea. Then I realize that the scientific literature does not contradict me. By the way, this means you must not be afraid to go against the scientific establishment. After deep analysis, I say to myself, “It is worth it to try,” and I do it. I mean I test it in my laboratory. However, I still always have a moment of uncertainty because I do not know if my idea will be validated by the experimentation. The joy comes when you see you succeeded, and after that, you say to yourself, “Yes, it was a good idea”. However, sometimes you have ideas that cannot translate to success. This time, though, my idea translated into a more efficient model.
So specifically you are injecting a cocktail into this mouse that will create the tumor. Tell us how that leads to a cure or a better way of treatment?
Dr. Doiron: In the field of cancer we are using animal models that came from the revolution of molecular biology, but this produced a transgenic or knockout mice model that poorly mimic cancer development in humans. Transgenic mice (in which you modify the embryonic development to create a cancer model) and embryonic knockout mice (in which you alter the embryonic development to knock out a gene’s expression) do not mimic the pathogenic mechanisms responsible for the development of cancer in adults. Therefore, these mice models are not well suited to the development of cancer that develops spontaneously with advancing age. In humans, one major factor in developing pancreatic cancer is aging. It is not something that develops at the embryonic level. Most pancreatic cancers are diagnosed between the ages of 60 and 80 years.
So, the transgenic and knockout mice models used today to test new medicine in pancreatic cancer are inefficient by essence.
My method takes adult mice and bypasses the embryonic development as found in transgenic and knockout mice models. By microsurgery developed in my laboratory, I inject the human cancer mutation directly into the pancreas of adult mice. That creates the same physiopathology happening in adults by developing spontaneous pancreatic cancer. So that mimics more randomly what’s happening in the cancer development. Now I have this powerful mouse model, and I can test new medicine with more predictability and accuracy that will have more chance to translate to effective human pancreatic cancer treatment.
The first time that you saw this actually started to work, how did you feel internally and emotionally?
Dr. Doiron: I made a little dance and jumped for joy. I was so happy when I saw it for the first time: “Wow, it works! “ So, it is a moment of joy. After that I sat down and thought okay, now I must push the project forward. It is a great feeling because the model can save lives in the future. My will to do science is based on intrinsic motivation to do better medicine. As Plato said, “Necessity is the mother of invention.” I understand the implication for people and families dealing with pancreatic cancer; we now have a model to find better treatments.
This is probably going to take ten or fifteen years before it gets done on human beings to help to treat pancreatic cancer. In the meantime, what will you do to move it to the market?
Dr. Doiron: At this moment I am in discussion with people who wanted to use my model with their creative mind to test new drugs. I do gene therapy, so I have some ideas to target cancer with innovative gene therapy. Science always progresses through a chain of events. Everybody will bring something. It could be in my laboratory or it could be in another laboratory. I am building on the hope that somebody in the scientific world including myself will come up with a creative idea. I already have an idea to test for cancer through gene therapy with my new pancreatic cancer model. Now I am searching for money to do my next step and test a new treatment for pancreatic cancer.
What is the discovery and how it is is it going to lead to better treatment or a cure?
Dr. Doiron: Working with an animal model that doesn’t mimic the human physiopathology of the cancer’s development in humans makes no sense. You can cure these inadequate mice models and have the grant money to do it, but it will eventually fail to translate into human application. It is easy today to create diseases in mice models that do not exist in nature or humans by using molecular biology techniques of overexpressing or suppressing gene expression. High failure in clinical trials in human cancer came from the inadequate animal models used to validate new medicine.
To have better predictability that new medicine will translate into success in humans, we need an adequate animal model that mimics the natural physiopathology happening in humans. So, to be able to do so, we need to mimic physiopathology mechanisms of what’s happening in humans. We need to mimic the random progression of cancer found in humans. Existing mouse pancreatic cancer models do not do that compared to my model. We need to mimic the human cancer mutations happening in adults without modifying the embryonic- level development. My model does mimic human cancer whereas another pancreatic mouse cancer model does not. Therefore my model can test a new medicine with the chance to have better predictability to succeed in human application.
My new pancreatic cancer model can be used to study metastasis formation as it happens in humans. It can be used to find a new medicine blocking metastasis progression. In cancer, two potential mechanisms are targeted for treatment. The first is to target the tumor formation directly into the tissues to regress it or eliminate it. The second target is to block the metastasis formation from reaching other organs.
My model mimics the metastasis formation that randomly happens in a human. Most mice models do not mimic this. A model used, for instance, is the graph tumor cell line injected into mice tissues. The tumor cell line is spread into the mouse body but creates metastasis localization that has nothing to do with human ones. A person obviously never develops metastasis by injecting himself with tumor cell line.
My new pancreatic cancer model presents two advantageous strategies: to kill tumor formation in the tissue before metastasis happens and also to test new medicine to block metastasis formation. If the tumors cannot create metastases, cancer will only grow locally into the tissue, and, in this case, it can be more easily extracted by surgery. So the new pancreatic cancer model has two fronts and strategic advantages because it can be used to target tumor formation into the tissues and block metastasis formation. We can envision in the future new cancer drugs targeting tumor growth in the tissues or blocking metastasis formation. Alternatively, a combination of drugs targeting both tumor growth and metastasis might be invented.
Can you describe the process of injecting the mice? Exactly what do you physically do and how long does it take for those tumors to develop?
Dr. Doiron: I designed microsurgery to inject the human pancreatic cancer mutation using a lentivirus. Therefore, the human cancer mutation is incorporated into the genome of the mouse pancreas. I targeted the pancreas and no other organs. Therefore I only created pancreatic cancer. After the mice incorporate the human cancer mutation into their pancreatic genome, they will develop cancer after 28 weeks. This delay in time before cancer development mimics the aging process in human pancreatic cancer formation. Don’t forget that mice age more rapidly than humans. The average life span of mice is three years. At 28 weeks you have old mice. Notice that 80 percent of mice injected with human pancreatic cancer mutation will develop cancer. My model offers a very cost-effective method compared to maintenance of a colony of mice for years.
In conclusion, we now have a novel human pancreatic cancer model with a cost-effective method to test new medicine for a deadly disease that definitely needs it.
END OF INTERVIEW
This information is intended for additional research purposes only. It is not to be used as a prescription or advice from Ivanhoe Broadcast News, Inc. or any medical professional interviewed. Ivanhoe Broadcast News, Inc. assumes no responsibility for the depth or accuracy of physician statements. Procedures or medicines apply to different people and medical factors; always consult your physician on medical matters.
If you would like more information, please contact:
Will Sansom, PR, UT Health San Antonio
210-567-2579
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