TGen Talks: Yun Rose Li, M.D., Ph.D.
Karie Dozer [00:00:03] I'm Karie Dozer and this is TGen Talks. Cancer. It's the second leading cause of death in the United States. And though advances in genomic medicine continue to make treatments more effective, TGen scientists are digging deeper. On today's podcast, we talk with Dr. Yun Rose Li, a physician-researcher who holds a joint appointment between City of Hope and TGen, and whose mission is to balance the benefits and side effects of precision cancer treatments, putting her patients and their priorities first. Dr. Lee is the recipient of the prestigious NIH Director's Award for Early Independence. A high risk, high reward research program for scientists pushing the boundaries of biomedical science. And Dr. Lee, it goes without saying you're a very busy person. Thanks for taking the time to talk to us. Can you tell us about yourself and about your work at TGen and City of Hope?
Dr. Li [00:00:52] So I'm a computational biologist, but also a physician-scientist. So I spend about one day a week seeing patients in the clinic. I primarily treat genital urinary cancers, so prostate cancer, bladder cancers, kidney cancers and so forth. And then the majority of my time I spend running a lab. My lab is somewhat of an integrated, what I call humid lab nowadays. So there's some component of dry and some component of computational work. And primarily what we try to do is try to understand some very basic aspects of the origins of cancer and how do things like oxidative stress drive both the development of cancer, but also how can we harness the power of oxidative stress to treat cancer in a safe way? Because of the radiation oncologist? We use radiation which is largely X-rays, and that X-rays, the power of X-rays actually is derived from the production of oxidative stress. And this has been a kind of a yin and yang issue for the majority of my training and career. A fascinating question, right? This idea that it's a double-edged sword, that simultaneously we are creating a process through which we can kill cancer cells, but that the very same process is also an initiator of cancer and can be very toxic and cause a lot of side effects. So part of my lab is really trying to understand the role of oxidative stress and its toxic side effects and its carcinogenesis and sort of the negative side effects and how we can mitigate that. But the other half is really trying to understand, you know, what are the ways to identify the biomarkers of response to oxidative stress and how to make cells or tumors more sensitive to oxidative stress.
Karie Dozer [00:02:26] This isn't the first-time math and genetics or math and cancer treatment have coincided on the podcast, at least with people that I've interviewed. Tell me how math. Tell me about how that competitive part of what you do. How does that factor into treatment of cancer.
Dr. Li [00:02:41] It's actually a big part. Right. And when we want it to be a bigger part than it is, because at the end of the day, we don't want the treatment of patients to be a catch all, which is still is in many ways. Right. The standard of care for the majority of cancers today remains essentially an algorithm. It's kind of a treat. You know, a patient has this they're at the stage. These are things that we do. But we know very well from a lot of data, both on the genetics or genomics side, but also on the clinical side that people respond very differently to treatments. And this by response, I mean both the tumor response and also the individual toxicities. And what we really want to do with a lot of the computational work is sometimes we want to be able to predict or prognosticate the outcomes of patients to a certain type of therapy. But also we want to be able to find new targeted therapies for patients based on their disease or individual characteristics. For example, some individuals may have a particular type of tumor that is likely to be responding to immunotherapies or a particular type of tumor that is more likely to respond to something called PARP inhibitors, which is an agent that's used in patients who have tumors or germline already deficiencies in DNA repair, and they capitalize upon that using a specific drug that makes it even worse for the cancer cell. And so these are ways to individualize or personalize cancer treatment. And I think we need to do more and more of that. And one of the challenges we have in radiation therapy is we don't yet have something like that. And that's one of my passions. You know, I think this is a career long challenge, right? It's not something that I can make an answer to in the next year or even five years or ten years. It's something that, you know, we strive for as a as a field and as scientists and clinician is really trying to bring that personalized level of care to the individual patient so that we can use upfront information about the patient's cancer and about his or her individual heritable genetic factors to determine what is the best line of therapy for this patient so that we can identify, you know, ways to treat patients without causing so much toxicity as cancer outcomes have gotten better and better overall. Statistically, it seems that patients are living longer, which is great. That's our primary end goal, right? They die of cancer. But now patients are actually facing a lot of side effects and chronic side effects. Some of these can be devastating. Dating, life changing and even can actually shorten their lifespan. And so because of that, it's particularly important that for certain cancers, for example, a lot of what I treat and care for prostate, prostate cancer patients and these patients, the majority of them do really well, but many of them, the majority of them actually have significant side effects from the treatment that often will linger on for the remainder of their lives.
Karie Dozer [00:05:25] The good news is they're living with the cancer. The bad news is they're also living with the side effects.
Dr. Li [00:05:29] Correct. And sometimes that that really drastically reduces the quality of their life, whether the problem is they have to get up and go to the bathroom five times a night, or the problem is that they have permanent erectile dysfunction. Right. These are life changing side effects. And so as a physician, you know, I try to think about what is the best thing for patients. And I think the best thing for patients is not just, hey, we want to slam the cancer and completely kill the cancer, but it's also what does that mean for the patient's quality of life? And everybody has individual goals, too. And that's another thing to consider as a physician scientist.
Karie Dozer [00:06:03] Quality of life isn't measured the same by every single patient.
Dr. Li [00:06:06] Yes. And there are many patients for whom say, like, if I lose this, I really don't want to live. Right. And that's really tragic to hear. But also it's a truth to that person writes how he or she feels about what's a quality of life they wish to lead. And so it's really important that we weigh these things when we think about treatment. And that's why in science, as we think more about personalized treatment, we try to shift that balance so that, you know, we're not going to lose the benefit we have or the efficacy we have in our treatment, but actually try to come up with a way to make the treatment less toxic, less likely to have these horrible side effects that patients ultimately live with. And I think that's really important because in my clinic, I think it's a it's a partnership, right between the physician and the patient. As much as I have that knowledge, I am not the patient. And I think the most important part in my job in the clinic is really to educate. And that's why I really like my particular job is that, you know, I get to play an important role in education, not only for the scientists and trainees in my lab, but for my patients. And that's actually why I ended up choosing this particular area of cancer, is because, you know, patients are generally pretty healthy, their cancers generally have good outcomes. And so it is a real partnership often for life, you know, that we discuss what are the risks and benefits of side effects, what are the risks of not treating the cancer, and how will their life play out and what do they expect to see in their life? And so being able to play a very important role in their decision-making process I think is a very crucial one for any physician to have a role in. And I really am honored that my patients trust me to play that role.
Karie Dozer [00:07:45] You mentioned the effects of oxidative stress on cancer patients. What is oxidative stress and what is its negative effect on someone's been diagnosed with cancer?
Dr. Li [00:07:54] So oxidative stress is a true yin and yang because at low levels it's actually present in every cell and in fact it is a necessary outcome essentially from it's a byproduct of our metabolism. As our cells are making energy, they inevitably make some leaks and in these leaks they produce these free radicals, which are basically very energetic compounds that are unstable.
Karie Dozer [00:08:18] And it's a buzzword. A lot of people have probably heard them.
Dr. Li [00:08:20] Yes. Yes. These things, these unstable compounds kind of try to attach to other things so that they become more stable. The goal of everything is to become stable. And unfortunately, those other things may be DNA, maybe other proteins or other fats that are in the body. And these just creates a cascade effect. This these free radicals kind of create other unstable molecules and things actually end up becoming more and more unstable. And as you can imagine, it creates damage in the tissue. And while the body is typically able to repair some of this damage, what actually happens is this repair process recruits an immune response. And so it creates an inflammation and this and then the immune cells generate more free radicals in its response. And so it's kind of a cascading effect. And how this becomes toxic is when the levels build up and the body is not able to stop this process. The body has a natural way to quench oxidative stress.
Karie Dozer [00:09:12] How do you measure that?
Dr. Li [00:09:13] So the question there actually many different laboratory tests that we can measure in cells anyways and tissues we can actually measure the activity in terms of quantifying how much free radical activity there is, but also measuring the how to how much chemical there is in the body to quench this. We can measure both size.
Karie Dozer [00:09:34] Because you measure the response, you're also measuring the stress.
Dr. Li [00:09:36] Exactly. But in terms of quantifying like, you know, in you or me, how much oxidative stress in the body, that's a lot more of an unclear question. You know, we can measure certain things like your general inflammatory profile and things like that, but being able to quantify oxidative stress is really more like on the tissue or cell level that we can go and quantify this. Ultimately though, it's somewhat we think. And one of the things I'm really interested in understanding is. Why are some cells or some tissues or some individuals more susceptible? We are all exposed to oxidative stress right through it. Like I mentioned, through our own metabolism, we produce these as a by part of a normal physiology. But some individuals go on to have these kinds of cancers that are driven by what we associate with chronic oxidative stress, which are things like bad diet and obesity. I mean, these are the biggest factors of what we consider productions of, of free radicals and oxidative stress. But there are also other things, you know, other environmental factors, other physiological factors. But not everybody is susceptible. It's just like not everybody is susceptible to cancer. And so what makes some people particularly prone, those are things that we still don't understand. And to answer your original question about, you know, what makes oxidative stress so bad? Well, what's interesting is that in cancer cells, they actually like oxidative stress, so they actually chronically tolerate a higher level than in normal cells, and they have developed ways to adapt to it. And some, some scientists actually argue that oxidative stress is a is a helpful thing that actually provides something useful for the cancer cells or others argue that it is a response of a changed. People have probably heard that cancer cells have a different metabolism. So some people believe that maybe this higher level of oxidative stress is more related and was a consequence rather than, you know, an egg, a chicken rather than the egg. Right. But others actually have this have new data suggest that maybe the oxidative stress is actually helpful to the cancer cell in some way. And so this, this is unclear. But what we do know is that it's a bad prognostic factor that that the higher levels of free radicals in the cancer cells are actually somehow associated with more aggressive disease, more higher rates of metastasis. And so that's one of the things that we know about oxidative stress is that in existing cancer cells, it's probably not a good thing to have.
Karie Dozer [00:11:58] You received something called the NIH Early Independence Award, which an insight from a science perspective is a pretty big deal. What does it mean? What did you in it for?
Dr. Li [00:12:07] The early Independence Award is part of it's one of four programs that is funded as part of the NIH director's Common Fund, as they call it. And basically, it's part of their high risk, high reward program. So, you know, what's really challenging about science these days is that it's gotten very competitive, but there's only so much research dollars to go around. So what ends up happening is that people have to submit grants that already have had a lot of preliminary data acquired almost to the point where when the when the grant goes in the papers about to come out. Right. But that's not really the point of the grant. The whole point of the grant is this is what you plan to do. You know, we have some data, but, you know, this is really a goal. Unfortunately, that's kind of gotten harder in this competitive environment because everybody has to prove that their research is more likely to succeed, has more data behind it. So then more recently, the NIH and other funding agencies and especially foundations, you know, philanthropic means of funding, people are starting to ask, well, what about sometimes the most creative or most innovative ideas are not the ones that have already had a lot of data. And in order for them to acquire that data, they have to have already had the funding. And so this idea came up that they should that the NIH director should create a common fund to try to fund these projects that may span the breadth of different research areas is not just focused on cancer or focused on heart disease or diabetes, but that it's really a project. It's a goal of funding projects that are innovative but don't necessarily have the data to fund it. So that's kind of the overall umbrella that it falls into. But the early Independence award is really more, I think, in many ways a funding for an individual and their institution because of a track record for both the individual and the institution of having demonstrated success in doing challenging science. And so and in my case, I was very fortunate that City of Hope and had supported me in applying for this award before I was even an independent faculty. So, you know, it was in between the time when I was still a resident and training and when I started as faculty here that I made the application. And so I received a lot of support from both institutions to put together this humongous grant, you know, detailing my dream science. And it really was because of their support that was possible because a lot of the questions that are needed to substantiate this grant is really like, you know what? What is the institution going to do in terms of its support? What kind of mentorship do they provide, What kind of facilities are they able to provide, How much research dollars is there? Are there shared resources in the cause that would allow you to do these research? So all of these questions were things I had no knowledge of, and so was really important to have had, you know, support from Dr. Steve Rosen, Doctor Dr. Mike Caligiuri, Dr. Geoff Trent to be able to, you know, build up this award, which, you know, was really a first for the institutions, you know, to have an early independence award. And so I'm really honored that they then. They supported me in making this application.
Karie Dozer [00:15:04] So that award is already benefiting the patients that you see in your clinic?
Dr. Li [00:15:09] Yes, because it's actually funding a clinical trial that's now open. One of the aims of that clinical trial was actually to test this idea that a metabolic intervention can actually improve the therapeutic outcomes of radiation. And so in patients that are getting what we call pelvic radiation, which is a large area of radiation to their pelvis for cancers of the rectum, of the prostate and of the cervix. And what happens in these patients is they end up getting some significant, often bowel side effects, but also urination side effects. And so the idea is, you know, can we come up with a way to reduce that side effect? And so the clinical trials actually testing something called time restricted diet, which is effectively intermittent fasting in the popular culture. And the idea is like if we ask patients to fast around the time of the radiation and stop producing, not stop, but reduce the production of the physiologic oxidative stress, can we save some of those normal cells from dying? And the idea is that if we can save enough of those cells that the toxicity wouldn't manifest as badly. And that's the clinical trial we're trying to do. And so it's an early phase study. We're accruing 60 patients and patients are going to be randomized to getting this very intensive nutritional counseling with app-based monitoring versus getting the addition of this intermittent fasting diet during their treatment. That's really the first phase of the test is really can patients actually get through the treatment with this on top? And that's why we have you know, it's like a nutritionist monitoring. We have them reporting help their hunger score on the app.
Karie Dozer [00:16:42] Keeping a food diary.
Dr. Li [00:16:43] Keeping all of these things, you know, trying to encourage patients to follow the diet just to see if they can even get through this before a bigger trial where we actually test efficacy can be carried out. And, you know, I'm really fortunate to be able to take care of patients because they are really the true inspiration. I see it in the clinic. I see the side effects they're dealing with, you know, patients who come back. And unfortunately, in order to cure them, I gave them a pretty significant side effect. And that breaks my heart. But I know I had to do what I had to do. But it also inspires me to think, like in the future there's got to be some better way so that I'm not causing this kind of toxicity. And that's really what pushes me along, is are those patients.
Karie Dozer [00:17:20] If there are better answers out there, I have no doubt that you will find them. Dr. Lee, thanks so much for your time. Really, really good to meet you.
Dr. Li [00:17:27] Thank you so much.
Karie Dozer [00:17:30] For more on TGen’s research, go to tgen.org/news. The Translational Genomics Research Institute, part of City of Hope, is an Arizona based nonprofit medical research institution dedicated to conducting groundbreaking research with life changing results. You can find more of these podcasts at tgen.org/tgen-talks, on Apple and Spotify and most podcast platforms. For TGen Talks, I’m Karie Dozer.