Disponible aussi en français: https://blubrry.com/fci_cfi/41971985/annie-castonguay-de-meilleures-molcules-pour-une-meilleure-mdecine/

Annie Castonguay, a researcher at Quebec’s Institut national de la recherche scientifique, works to mobilize metals to destroy cancer cells and drug-resistant bacteria when traditional antibiotics and cancer treatments fall short.

Cancer treatments like chemotherapy aren’t perfect. The drugs meant to kill cancerous cells aren’t choosy, so they take out healthy cells too, which can mean serious side-effects for the patient. And if cancer cells develop a resistance, the therapies might not result in a complete remission. Engineering new molecules that incorporate the power of metals to destroy diseased cells could not only lead to more effective cancer treatments, but also better defences against another serious health threat — multidrug resistant bacteria.

Return to the collection

00:00:05 - 00:05:02

This podcast is brought to you by the Canada Foundation for Innovation.

My name is Annie Castonguay and I'm an Assistant Professor of chemistry at INRS institute Armand Frappier. Metals are at the heart of Dr. Annie Castoguay's research. Her programme involves both fundamental and applied research. She is interested in the design of new organic metallic complexes for their use as catalysts and as therapeutics such as anti cancer and antimicrobial agents. She and her collaborators at the INRS Institute Armand Frappier are engineering new molecules to overcome some of the problems with current cancer therapies.

Unfortunately metal complexes often have a bad reputation as therapeutic agents. Very often people mistakenly believed that they are too toxic to be used in medicine. What they do not know though is that metal complexes are widely used in clinics every day. It is reported that approximately fifty percent of all cancer patients who undergo chemotherapy are at some point treated with a metal complex. So for example a compound known as cisplatin which contains a platinum metal atom which is widely used in the world for cancer therapy. The compound is injected to the patient intravenously undergo some transformations and reaches its main target believed to be DNA so then the cancer cells die and the patient survives. Unfortunately there are many problems associated with chemotherapy. As we know firstly therapeutic agents become less and less effective due to the development of cancer cell resistance. Cancer cells learn how to recognize the drug and adapt to survive in its presence so moreover theraputic agents are not only toxic to cancer cells but are toxic to healthy tissues as well leading to numerous side effects. I wish i could say that researchers have now solved all these problems. But unfortunately this is not the case. The part of my research program which aims at developing novel anti-cancer drug candidates attempts to address those two problems. So my team develops compounds based on routeenium. Some routeenium complexes are known to linked to DNA but also to act through other modes of action so previously reported routeenium complexes were found to be very promising as drug candidates and some of them even in third clinical trials during the last few years. For example, an ongoing research project in my lab involves the preparation of multitasking metal complexes which consistent in the synthesis of compounds based on routeenium to which are coordinated molecules that can themselves display an anti-cancer activity. So the creation of metallic compounds able to act through different mechanisms simultaneously could lead to the development of new efficient treatments that induce less cancer cell resistance.

Another ongoing project in my research group is the design of metal complexes that can display a higher selectivity towards cancer cells so to reached his goal we create thermal sensitive linkages between metal complexes and targeting molecules which can be disassembled at higher temperatures so those targeting agents with the special affinity with cell receptors or orginels of certain cancer cells are carefully chosen so that they can act as shuttles and helped the metal complexes to reach cancer cells or tumors more efficiently before being released either slowly at body temperature, thirty seven degrees or more rapidly with the use of a laser. So we hope this strategy to be beneficial for cancer patients by reducing the occurrence of side effects during their treatment.

Dr. Thomas Sanderson is a professor of toxicology and he works with Dr. Castonguay at the Institute Armand Frappier. They hope the complex's they're testing will also work at starving ER positive breast cancer cells of the estrogen that they need to grow.

And the other action of the same molecule would be to enter the micro environments of the tumor and enter the cells around the tumor that are actually producing the estrogens that feed the tumour and the enzyme involved there is called aromatase and the organic metal compounds that is producing have several aromatase molecules attached to it which are then released in these cells at least, that is the hypothesis and we'll be able to inhibit the enzyme that feeds the tumour

00:05:02 - 00:10:28

So if one of the components the mental part that is killing the tumor cells directly and the second components, the aromatase inhibitor. that prevents the food source of the tumor by inhibiting the enzyme in the in the surrounding tumor cells.

This type of research is a painstaking process. Dr Castonguay explains that she and her colleagues are closer to the start than the finish in terms of developing a viable chemotherapy alternative.

We didn't reach to the point where we would test even our best drug candidates in mice. What we do for now is that we do in vitro studies and we also started to work with zebra fish models. So these are kind of accepted in vivo studies. Preliminary toxicity studies for drug design.

Dr. Castonguay's work at the Institute Armand Frappier flows from a lifelong fascination with the scientific world. Her quest to understand the world around her began as a child long before she started building molecules.

I come from Grandby which is a city located in between Montreal and Sherbrooke in Quebec. And i've always been interested in science. I remember finding myself in the basement of my parents house trying to challenge myself to work on a specific topic and try to learn as much as i could on the topic. Just by reading some of these Encyclopaedia that were available to me in that basement. I remember that I was interested in astronomy. Biology also in chemistry but not specifically in chemistry. I decided to go to Champlain regional college and i registered to a very broad scientific program.

After that i started university and i went again to a general program because i chose to go in chemical engineering and so i i registered at the Ecole Polytechnic de Montreal and during that year and a half I really missed chemistry. I really understood that chemistry was missing. I really wanted to learn more about interactions between molecules so i decided to move on and registered to a bachelor degree in chemistry.

So i registered to invest in Montreal, the building right beside but i remember that what really really caught my attention and what was really the highlight of my bachelor I would say was to take this course in the second year about mineral chemistry inorganic chemistry. It was a lab. I remember that I was amazed by the chemistry of metals. So after i decided that i really wanted to do a master degree in chemistry of metals so i chose to work with the group of David Sagarian at the University de Montreal and i also was directed at the time by Andre Beauchamps who is also very good inorganic chemists.

So i worked with them I had an amazing time during my phd. I learned a lot of things. The main goal of my PhD was to prepare metallic complexes based on nickel which is a metal and i had to prepare... designing some complexes that we're going to be active to be catalysts for organic reactions so after my PhD I went to Tufts university in Boston and the during the training I worked with Molybdenum complexes. Molybdenum is another metal. It was a very challenging. When I was using a glove box so I had to work under inert atmosphere so i had to get very skilled at working with such compounds.

Dr Castonguay's research into organic metallic compounds is driving cutting edge collaborations with scientists from a range of disciplines within the INRS. She began seeking out connections as a postdoctoral fellow where she worked at the intersection of chemistry, biology and therapeutics.

I undertook to other post docs and both of them were at Mcgill University. The first of them was when i started to get more experienced. I would say a with organic synthesis and i undertook a very challenging project at preparing dendrimers. So I worked at preparing dendrimers that would have antimicrobial properties. So this is when i started to enter the world of biology and then i started to work with the collaborator of the group from do pharmacology and therapeutics department from McGill for my third post doctoral project so i was for the first time exposed to cell culture I was working with students would grow cancer cells in cell culture labs so that was very interesting to me.

00:10:28 - 00:15:02

I really enjoy doing that.

When the INRS was seeking a professor of chemistry at the Institute Armand Frappier Dr. Castonguay said she was intrigued by the opportunity to work alongside so many different types of scientists. Her cross discipline research was seen as an asset.

My experience in biology during my post doctoral studies allowed me to become interesting for people who were working here. And i found that i could establish a lot of different collaborations in different areas because i was a chemist, I was able to prepare molecules... interested in metals but i saw I had experience with anti-microbials in anticancer compounds. So here there are many researchers working in those areas along with immunology, toxicology, environment, .... There are all sorts of of research here.

So i discovered that this place here was the size of a university department but there were so many different expertises in so many different fields of research.

Metals may also be an innovative weapon in the fight against multi resistant bacteria. Dr Castonguay is testing some of her molecules on bacterial pathogens.

Yeah as we know there is currently in an urgent need to develop new antibiotics that are active against multi-resistant bacteria so organometallic complexes are according to me not studied deeply enough for that purpose and this is why my group establishes collaborations with microbiologists from INRS with the hope to discover molecules with novel modes of action.

So it was previously reported that some metallic complexes can interact with DNA... some enzymes and disrupt bacterial membranes. Complexes prepared in my lab are then tested against various multi resistant bacteria and some of those compounds recently screened were found to be highly active and selective against important patterns.

Dr Frederic Verier is a researcher in microbiology at the Institute Armand Frappier. He's working with Dr. Castonguay to test compounds that may offer a much needed treatment for people infected with antibiotic resistant bacteria.

So the research of professor Annie Castonguay is original in the sense that she synthesize organometallic molecule that are for the moment underexploited for the antibiotic properties. There are multiple evidence that this molecule could be the source of new antibiotics with ... properties. So with Annie we have already carry out several screen of different complex prepare in her laboratory to extract ... complex with bacteria... activity so we are now looking for the mode of action with the the hope that the mode of action we'd be original. And we also hope to discover molecules that act on several different targets simultaneously to avoid evolving resistance in the future. So in fact we have already identified a very promising molecule extracted from the screen which will soon be the subject of baton given it's high activity but also it's high selectively for some ample time pathogen specifically....

The professors INRS Institute Armand Frappier conduct their research in every corner of the scientific realm. But when Dr. Castonguay joined the team she identified a need for chemistry equipment that would make her work more efficient and she credits investments from the Canada Foundation for Innovation and the Quebec government for funding a suite of tools that are essential for the research she and her collaborators are doing.

I'm very lucky. I got a lot of equipment and without that the equipment I would not have been able to make any of the research I'm doing right now. With what was what was available at the institute when i started because as you know there were not that many chemists here and that definitely not doing the same chemistry as I do. So as i mentioned earlier we have to prepare compounds under inert atmosphere.

00:15:02 - 00:17:02

So we have a trio of three really complimentary pieces of equipment. It's great now now that we are all fully equipped. It's very very nice. It's completely different than when i started four years ago. I mean there are many advantages for chemists to be here that's for sure but the downside is that if we need something that is chemistry related we cannot borrow it. We cannot use it from somebody else. We have to be self sufficient so this is where CFI was really really essential for me to be able to undertake my research program here because definitely yeah. I could not function if I could not have all that.

We just want to emphasize on the fact that it's very very important for an early career researcher to be able to have to be allowed to apply for that equipment that CFI is providing because it is extremely important not only to be able to undertake the projects that these early researchers want to do but also to keep them at a competitive level with the other early researchers from other countries for example or other labs.

The investments the CFI has made to further Dr. Castonguay's research help keep her on the leading edge of scientific study and in time, her innovations with organometallic complexes may offer new hope in the fight against cancer and drug resistant bacteria.

Find more research stories like this at innovation dot ca slash stories and subscribe to the Canada Foundation for innovation through your favorite podcast app.