From bench to bedside: translational research on TRP channels in chemotherapy pain
September 27, 2024
Chemotherapy-induced peripheral neuropathy (CIPN) is a debilitating side effect experienced by many cancer patients undergoing treatment. Despite its prevalence, effective treatments or preventive measures remain elusive. For Pain Awareness Month, we chat with Heleen Marynissen and Silvia Pinto who are researching the role of TRP channels in CIPN. By bridging the gap between rodent models and human studies, their research offers promising insights into this condition.
Hi, Heleen! You've recently completed a PhD project on the role of TRP channels in chemotherapy-induced peripheral neuropathy. Could you tell us more about CIPN?
Heleen: CIPN is a debilitating pathology that many patients experience after receiving specific kinds of chemotherapy drugs. These drugs are the first line of treatment for several types of common cancers, such as breast and colorectal cancer. On average, two out of three patients who receive this treatment experience peripheral neuropathy as a side effect, accompanied by symptoms such as numbness, tingling, and sometimes allodynia. Allodynia is a phenomenon where people experience pain from what would typically be a non-painful stimulus. For instance, what should be a feeling of cold from opening the fridge, or a bit of pressure from somebody squeezing my hand, would be extremely painful for these CIPN patients. For every one in three patients who experience CIPN it becomes chronic, which massively affects their quality of life. As of right now, medicine has nothing to treat or prevent it.
What did your PhD project focus on specifically?
Heleen: Most of the research that has been done on this phenomenon so far has been done in rodent models. This work has been very important for understanding which specific TRP channels are involved in this kind of pain, and how their underlying mechanisms work. This preclinical research indicated that TRP channels might be more expressed or sensitized on peripheral nerves after chemotherapy. My project, supervised by Jan de Hoon at the Center for Clinical Pharmacology in the UZ Leuven hospital and Thomas Voets at the VIB-KU Leuven Center for Brain & Disease Research, aimed to take the extra translational step from rodent models to humans.
To do this, we used a non-invasive technique to assess TRP functionality in patients by topically applying a droplet of cinnamaldehyde, a compound of cinnamon, and capsaicin, the ‘hot’ component of chili peppers. If you apply them on the skin, these compounds diffuse through the skin and reach the TRP channels that are expressed on peripheral nerve endings. If the TRP channel is activated, the nerve ending releases specific factors which then affect the blood vessels, causing the skin to become red. We can measure the redness of the skin using laser imaging techniques and use this as an indirect measure for TRP functionality. This way, we could investigate differences in TRP channel functionality between people who received chemotherapy and those who didn’t.
While Heleen led the clinical aspect of this research, Silvia conducted the animal research in the lab. Can you tell us more about this?
Silvia: My contribution was regarding the animal handling and behavioral tests. At the Thomas Voets Lab, we have several years of in-house rodent model expertise to study TRP channels specifically. We used this expertise to complement Heleen’s research with people in the clinic. With our rodent models, we were able to replicate Heleen's findings in humans and delve more deeply than was possible with patients. After conducting similar tests with the rodents as Heleen described with patients, we could study the neurons of the rodents in detail to better understand what is happening at the molecular level. This gave us valuable data and much more information than studying patients alone.
What were the most exciting results from the research?
Heleen: For me, the most exciting thing was to see that our clinical results were fully in line with previously published data from the preclinical research. The redness of the skin, and thus the TRP response to cinnamaldehyde in patients was indeed significantly higher compared to healthy controls. This confirmed the hypothesis that chemotherapy drugs (in this case, oxaliplatin for colorectal cancer) really affected TRP channels (specifically, TRPA1) in patients. Therefore, TRPA1 has a high potential to serve as drug target to treat CIPN. Investigating the effect of a TRPA1 antagonist in patients with CIPN after oxaliplatin would thus be a very interesting next step.
Silvia: It was also exciting to see the results correlate to what we saw pre-clinically in the rodent models. We could mimic a specific human pain condition in rodents and obtain objective data to understand the pain mechanism. In these models, we could also look at the neurons and see that the in vivo functionality was also increased. It confirmed the reliability of the rodent model for studying this type of pain in more neurobiological detail.
Why is it so important for "bench to bedside" (lab to clinic) collaborations for pain research?
Heleen: In pain research, there is a very large translational gap. The pathophysiology of pain, particularly neuropathic pain, is very difficult to study. Rodent models are very important to help us understand what's going on at the molecular level, but can only tell us so much about what humans experience. On the flip side, tools for studying pain in humans are more limited, which makes rodent models still really important to our understanding of pain and developing therapies to combat it. Being able to implement the same method in rodents and in humans partly fills this gap.
Silvia, you recently became head of a new expertise unit for Rodent Behaviour at the VIB-KU Leuven Center for Brain & Disease Research. Can you tell us a bit more about the services you offer?
Silvia: Absolutely! This is a fantastic opportunity because we are now better equipped to share the knowledge and resources that we have been developing for years in the Thomas Voets laboratory. We're keen to help researchers with the design and to run experiments using live animals, share our expertise, equipment and support throughout the process. Our facilities are close to many labs based at the hospital, making it logistically easier for researchers and more comfortable for the animals as well. We have several equipment including open field for locomotion studies, elevated plus maze for anxiety assessment, and pain rodent models, including inflammatory and nerve constriction models. We are integrated into an extensive research network including the Mouse Expertise Unit (MEU), Mouse Behavioral Phenotyping Core (mINT), and the Laboratory Animal Center (LAC). Feel free to get in touch if you'd be interested in collaborating!
Read more about the animal models our researchers use