Lidocaine May be a Valuable New Tool for Cancer Treatment
In an interview with Targeted Oncology, Ryan Carey, MD, and Rob Lee, PhD, discussed the preclinical research and the potential for lidocaine to kill certain cancer cells.
Ryan Carey, MD
Findings from a study demonstrated that T2R14 is particularly elevated in head and neck squamous cell carcinomas associated with the human papillomavirus, suggesting that lidocaine may have potential as a novel therapeutic agent for cancer.1,2
Lidocaine is a safe and well-tolerated common local anesthetic that has been shown to activate the bitter taste receptor T2R14 in cancer cells. The activation of T2R14 leads to an increase in mitochondrial calcium, which can trigger cell death through a variety of mechanisms.
Previously, research showed that by injecting lidocaine around an early-stage breast cancer tumor before surgery, overall survival and disease-free survival could be improved.
Now, experts including Rob Lee, PhD, and Ryan Carey, MD, found that in head and neck cancer cells, lidocaine-induced cell death is mediated by inhibition of the proteasome, a cellular machine that degrades unfolded or misfolded proteins.
Further research is needed to determine the efficacy of lidocaine in other types of cancer, and to further optimize its use in combination with other therapeutic options, a clinical trial is being planned.
In an interview with Targeted OncologyTM, Ryan Carey, a head and neck surgeon at the University of Pennsylvania, and Rob Lee, an assistant professor of Otolaryngology at University of Pennsylvania, discussed the preclinical research and the potential for lidocaine to kill certain cancer cells.
Robert J. Lee, PhD
Targeted Oncology: Can you provide an overview of this research and what led your group to study this topic?
Lee: We studied how taste receptors are expressed all over your body in different tissues, and these receptors are called taste receptors because they were discovered in your tongue. They're known to be all over your body. They do all these different things. We've been studying them in the context of first immunity in the nose. Ryan joined the lab a few years ago, when he was a resident before he was actually a full-time attending faculty member and started looking at them in the context that they've been known to be expressed in the oral or the gum epithelium. He's interested in head and neck cancer, so he wanted to look at these receptors in that context.
We started to determine that the receptors were expressed in these cells from [patients with] head and neck cancer, as well as cell lines in vitro. We started to study how the receptors activate apoptosis, which is the cell death pathway, and he also correlated some of the expression of some of the receptors with patient survival outcomes. Building on that, Zoe Miller, the pharmacology grad student who's the first author on the paper, who did 99% of the experiments in the paper [was given] the lidocaine study because it had been known to taste bitter, and we had discussed some of the aspects of bitter anesthetics that are used in in certain oral cancer surgeries. Lidocaine has been known to taste bitter, but it's also been known to have some sort of mysterious, beneficial anti-cancer effects, largely in vitro models.
We found that lidocaine activates this receptor T2R14, and Zoe showed very elegantly that this drug activates, specifically, this 1 bitter receptor, which is interesting because we have 25 different bitter receptors, and a lot of the drugs are cross-reactive between different ones. Lidocaine is a potent activator to T2R14, which is great, because from an anticancer perspective and because it's expressed in almost every cancer cell across everything that's in the Cancer Genome Atlas, we've yet to really find a tissue that doesn't express this specific bit of receptor. We think this might be useful as a potential therapeutic in some settings.
Carey: With the breast cancer research that's been done, there was a nice, randomized controlled trialwith multiple institutions that came out in the Journal of Clinical Oncology this past spring. That was based on the fact that people had observed that in breast cancer, lidocaine in the lab killed breast cancer cells and prevented migration of the cancer cells. Separate work had shown that breast cancer expressed T2R14, but the trial was not necessarily motivated by those studies on the bitter taste receptors.
Because people had seen that there was this killing response from the lidocaine, they decided to design this trial. That trial showed that if you inject lidocaine around an early-stage breast cancer tumor, prior to removing it surgically, those patients had close to a 5% improved overall survival and disease-free survival, which is an impressive survival difference with such a simple intervention. Whenever I'm doing a biopsy in the office, I'm using lidocaine to help numb up the area. People that have had dental work often remember having lidocaine for that. It's something that we use all the time, but we rarely think of it in terms of a cancer benefit; we just start doing it to prevent pain. To be able to use a commonly used medication, a drug that has great safety data already available, and repurpose it for its potential cancer benefit is exciting for us. It's simple to implement, and it's something that we're going to explore in the cancers that we treat related to the head and neck.
Can you discuss the specific mechanisms by which lidocaine activates the bitter taste receptor T2R14?
Lee: The activation of the receptor is just lidocaine binding to the receptor. The mechanism is really in the apoptosis. Lidocaine activates this big intracellular calcium response. Calcium is a master signaling molecule in a lot of different cell processes. What's unique about the bitter taste receptors is that they increase mitochondrial calcium, so you have calcium that gets released into your cytoplasm that then can regulate different things, and some of that can also go into the mitochondria. The bitter receptors and the activation of T2R14 by lidocaine causes a massive overload of calcium in your mitochondria. Your calcium needs some mitochondria function, but some of your mitochondria need some calcium to function, but too much is actually toxic, and the mitochondria go nuts, they produce tons of reactive oxygen species, and this can cause different mechanisms of cell death.
The mechanism that we're seeing involves inhibition of the proteasome. Increased mitochondria-reactive species can damage the proteasome, which is a cellular machine that degrades unfolded or misfolded proteins. It's the target of a lot of cancer drugs, like bortezomib [Velcade]. Inhibiting the proteasome directly is known to be able to kill certain types of cancer cells. Lidocaine does the same thing through this pathway with T2R14.
Lidocaine, as it functions as an anesthetic, is known to block neurons from firing. It inhibits voltage-gated sodium channels, the neurons can't fire, [and] it doesn't make sense that it would kill a tumor cell if that's the mechanism. It shouldn't have any effect on a tumor cell, which may express very little or almost no voltage gated sodium channels. This is kind of new, and as pointed out, even the clinical trial that was done with lidocaine, there's really no justification to use it, except for the fact that we've seen it kill some cancer cells in some settings. We hope this opens up more clinical work, because now that people know there's a mechanism, maybe people will continue to explore other cancers as well.
Cancer Cell: © vitanovski - stock.adobe.com
Would you be able to discuss the significance of the findings and kind of the implications for them for cancer?
Lee: For most head and neck cancers, we treat with surgery, radiation, or chemotherapy, or some combination of those. There's been some exploration of more targeted therapies, but for the most part, they've had mixed results. Unfortunately, many head and neck cancers behave badly and many of our patients succumb to the disease. Even those that we are very successful with treating, or what we consider to be successful, they're still sometimes left with quality-of-life factors, things like issues with swallowing, speaking, needing to have a tracheostomy or a feeding tube. Sometimes we see that in our patients, even the ones that go on to live and are cured of the disease, they're still impacted by it. Anytime that we can find something that doesn't have as many [adverse] effects or that can help boost our ability to cure this challenging cancer is extremely appealing to us.
As for the implications for head and neck, we treat tumors of the upper aerodigestive tract in areas that you can access. Unlike a tumor of the breast, for the oral cavity, a patient could irrigate their own mouth with a lidocaine mouthwash, for example. I'm not suggesting that patients do this, but these are the types of things that we're thinking about as a way to take advantage of the anatomic differences and the unique aspects of cancers of this region. They are in areas where I could see the tumor and could potentially inject something around it. We're not we're not suggesting that lidocaine is going to solve all of the problems, and is going to be used in isolation, but in order to kind of enhance our ability to effectively cure these cancers, and also limit the [adverse] effects of treatment, this might be a potential tool for us. Lidocaine is something that's already used and is available, so there's fewer steps that might be necessary to get it to the end user to the patient.
How does this study kind of fit into the broader landscape of cancer research?
Lee: I would just think about drug repurposing as drug repurposing is really hot. We're repurposing a very safe, used drug for novel anticancer purposes with a new defined mechanism.
Carey: We're trying to solve a problem that people have been trying to solve for many years, but we're trying to approach it in a very different way. Yes, we're repurposing things, but we're talking about a pathway. The study of taste receptors in tumors is something new [and] we were 1 of the first groups to study it at all. We're trying to solve a problem from a different angle. We're hopeful that by doing that, maybe we can overcome some of the obstacles that exist with these tumors.
What are some challenges that you either see in the future of this research or just moving forward in general with the space?
Carey: This receptor is repurposed throughout the body for different functions. We're learning that different tissues use it for different purposes, and then cancer cells, this receptor is kind of rigged up differently. Anytime we're talking about a drug, you want it to be specific and target the tissues where you want it to act. Of course with chemotherapy, that affects many cells in the body, but you're trying to target the ones that are rapidly dividing like cancer. For us, thinking about how we target this, specifically to the tissue or the cancer, that tissue of interest is going to be an obstacle. That's why we're fortunate that we're working with a compound that can be injected locally.
Based on these findings, you're planning to develop a clinical trial. What can you tell us about this potential study?
Carey: We're very much still in the preliminary phases [and] we're working on the design of it. One of the things that Zoe's paper identified was that this receptor is elevated in HPV-associated squamous cell carcinoma, which is on the rise and is a hot topic in head/neck because it's increasing in incidence. Fortunately, many patients do well, but some of them unfortunately don't. Having therapies that are less toxic is really appealing. We're kind of focusing on that group, knowing that they appear to have higher expression of this receptor.
We're hoping to potentially use lidocaine in the operating room, injecting into the tumors or around them to help activate this potential cancer killing effect. still treating them with the same treatments otherwise, but maybe this additional intervention will help improve their outcomes. We're working on the design and we're hopeful that we get it up and running in the near future, but it takes time to translate from bench to bedside, and we're optimistic and working on it.
Looking forward to further research in the space, what would you say community oncologists should take away from all of this?
Carey: Anytime that somebody is diagnosed with cancer, whatever it might be, it's good to make sure that they're being seen by somebody who specializes in that space. We're fortunate at Penn that we have people that only focus their entire career on a certain type of cancer. Those of us that focus on 1 cancer are able to be kind of in-the-know about all the hot topics. Still, it's hard, but by connecting with somebody who specializes in it, they might know about a trial like this that might exist. At Penn Medicine, we're always happy to have conversations with people out in the community, and [we are] always happy to help with care of patients and are always happy to see patients that might need sort of a specialized outlook on things.
What are the key takeaways from this research?
Lee: [There are] 2 key takeaways that might be of interest. One is that there [are] still receptors, there [are] still proteins in tumor cells that we're only just learning about and what they do. We don't know everything about tumor cell biology. The second point is that sometimes we can take insights from the lab and translate it to the clinic, which is what we're trying to do, but sometimes you also take insights from the clinic, and translate it to the lab, which is a lot of what this lidocaine stuff came from because people had observed the facts, and we tried to set out and determine the mechanism. So that can go both ways. I think that it just speaks to the importance of physicians and scientists working together in this space to develop new therapies based on each other's observations.
Carey: Patients, when they're diagnosed with cancer, they're looking for solutions. Sometimes a patient might feel like they're in a vulnerable position where they are just trying to grab anything that might help them. These types of things should be evaluated in a clinical trial setting with the right oversight. We're excited that we're going to be able to provide that in the coming years through our work, but patients should talk with their doctor and make sure that they're sort of doing the right thing for themselves.
[Also] as we mentioned at the beginning, Zoe Miller was the one who spearheaded this work. She has been phenomenal, and we've been fortunate to get to work with her. She's really moved this forward. It's so impressive what she's accomplished in the period that she's been in Rob's lab, and we're optimistic about what she'll accomplish in the next year and in her career.
