Smart Athlete Podcast Ep. 84 - Dr Robert Doebele - TARGETED THERAPY

What was challenging about the decision is that I was giving up seeing patients. And that has been a motivation and an inspiration. I treat cancer patients who, for the most part, have metastatic disease, which means that they’re sadly going to likely die from their cancer at some point.
Smart Athlete Podcast Ep. 84 - Dr Robert Doebele - TARGETED THERAPY

ROBERT: [00:01] What was challenging about the decision is that I was giving up seeing patients. And that has been a motivation and an inspiration. I treat cancer patients who, for the most part, have metastatic disease, which means that they’re sadly going to likely die from their cancer at some point. The good news is we’ve been able to extend survival significantly, but it’s always hard leaving patients. And I’m so grateful that I have been able to take care of wonderful patients over the course of my career, and they’ll always serve as a motivation for what I do in terms of drug development, and always keeping them as the kind of central focus of why I do what I do.

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JESSE: [01:36] Welcome to the Smart Athlete Podcast. I’m your host, Jesse Funk.
My guest today is a Former Collegiate Swimmer. He actually has a dual degree. He has his Ph.D. in Immunology and he has his medical degree, so in every sense of the word, he is a doctor. Currently, he’s a Chief Scientific Officer of Rayne Therapeutics. Welcome to the show, Dr. Robert Doebele.

ROBERT: Thank you. Thank you for having me.

JESSE: [02:00] Yeah. Thanks for hanging out with me. I know you said before we got going that you’re headed off to ski this weekend. So, you’re taking the last moment to hang out with me before having a hopefully, very enjoyable weekend. So, I really appreciate you spending a little bit of time with me.

ROBERT: Absolutely.

JESSE: Yeah. So, I do want to give you a little bit of a hard time just to start off. And I saw on your Twitter account there was a picture of a puppy that you had posted asking about whether you should get this puppy and I think your daughter and puts you up to putting a pole up. So, I’m wondering if it was an honest poll if, you know, say you put it up and your like, if it says yes, I’m definitely getting it. If you already determined you’re getting the puppy like, what’s the story there? I feel like getting a pet seems like a big chance to leave it up to the internet to say yes or no.

ROBERT: [03:01] Well, I think my daughter — my nine year old daughter is very savvy. I think she knows, you know, even my scientific Twitter audience was going to go for the puppy. And so I think she played me there. We were leaning towards the puppy, you know, that helped push us over the edge.

JESSE: It’s just, you know, I think when it comes to the internet that you’re gonna find very few people that like see baby animals and go “No, I hate that. Don’t be involved with baby animals in any way.”

ROBERT: Yeah. And you may hear Joey barking in the background now since that poll. But the puppy did happen.

JESSE: [03:49] But we obviously won’t see him because we got the nice background behind you. Before we going too, we were talking about swimming. I was asking about kind of about your background because I talked to any number of levels of athlete anywhere from basically I’ll say average Joe that’s not quite accurate but all the way through pros. And you’re telling me you only spent a year swimming in college. Can you tell me what happened there? You know, [inaudible 04:4] after a year.

ROBERT: Yeah. So, you know, swimming is often for people a lifetime sport. I would say I started actually on the late side. I started when I was nine years old. And so a lot of my colleagues in swimming probably started at five, six, seven, eight. My kids started a little bit earlier.

And you know, I swam very seriously in high school. I had a very intense coach who doubles and triples over Christmas holidays, practice Christmas morning, despite the fact that we went to a Catholic school. And I think when I got into college, I was excited to swim in college but was plagued by a bad right knee. And knee injuries are not the first thing that comes to mind. When people think about swimming injuries, it’s mostly shoulders.

And I was a breaststroker, unfortunately, and breaststroke has a kind of an odd lateral move in the knee and can really put a lot of torque on the knee. And that’s the injury that I was plagued with. And as I tried to do more butterfly and freestyle and other strokes to compensate, then I started dealing with some shoulder issues. And I guess between that and having fun and other things to do in college I’d say that’s what ended my swimming career, ended my collegiate swimming career. Luckily, I have come back to it and still love doing it now. Now it’s a bit of an addiction, actually. But —

JESSE: [05:55] Yeah, you know it’s — I hadn’t thought about this when you first mentioned it and as we’re talking about it again here, I was kind of curious, like, so you’re a breaststroker. And obviously, people seem to often specialize, like this is a stroke I do, like this is it and you build up certain muscle groups for that specific stroke.

Do you, because of injury or personal preference, do people ever or often make a crossover between say, like, in your case you’re doing the other strokes and that can lead to other problems? Is that common where in, again with your case, with breast stroking, if you have knee injuries, okay, well, let’s stop doing that. I’m gonna go freestyle or fly or back, even. And just say, “Hey, I’m gonna, relatively speaking suck at this for a while and then get better.” Does that happen?

ROBERT: [06:50] I mean, people definitely cross over like I was a breaststroke or — and breaststroke’s an odd stroke, right? It’s so different from butterfly and freestyle and backstroke. I mean, it’s double-arm, it’s underwater. It’s very unique. And maybe I’m just an oddball, and a glutton for punishment. So, I’d say people do switch over.

But again, the more common injury is shoulder injuries, and that’s hard to do anything else. You know, I’d say, it’s rare that like a backstroker probably becomes a breaststroker or such. I think the practices tend to be more freestyle heavy.

And in high school, I found out that butterfly was — kind of came naturally to me. I don’t know again, if it’s the kind of simultaneous arm movement or something else. But I transitioned a little bit into a butterfly in high school. And that was a good thing for me too. But I’d say it’s not terribly common, but there are specialists and there are some people who are just good at everything, you know, people who do the IM or at least very good at all four strokes.

JESSE: [07:58] Yeah, yeah. I guess that’s a fair point where it’s, again, I’m just like, I’m trying to think this out on the fly. And I guess it makes sense. If you’re in one of the other strokes, not breaststroke, and you hurt your shoulder, well, like your main — your arm is out, there’s no, like one-arm stroke. We’re not like doing the sidestroke down the pool or anything.

Like non-competitive kind of, what would that be a rescue swim, where you can only swim with one arm. Although maybe we should start that, maybe that’s the event for injured swimmers where you’re like, all right, everybody that’s injured, you’re all like injured reserve, you can go to this event, and it has to be one arm only.

ROBERT: [inaudible 08:38] Well, there was that short time, when you could kick underwater the entire length of the pool and come up for like one stroke. And I actually had a — and that was when I was in college, you could do that. So, I had a friend who I think he was a senior when I was a freshman, who is a really good backstroker and freestyler. And he was such a phenomenal kicker despite his shoulder injuries, he was still a phenomenal collegiate swimmer because he could kick so well. And that was the time when you can do the entire underwater kick thing.

JESSE: [09:10] That’s one of those things where the sport kind of evolves and I’m not really in swimming. But if you’re even farther out than I am, and you’re like, wait, like what happened — I don’t understand. And you — so those are regulations about because kicking is so effective speed wise compared to I would think especially breaststroke, you can’t just go down the entire pool, you actually have to do your stroke.

And I don’t know the specifics now on like, you can only go so far and that kind of stuff. But it makes sense when there’s essentially a way to circumvent having to do your stroke and still be competitive that eventually, the governing body would be like, “Yeah, this isn’t happening more like we’re putting a stop to it.”

ROBERT: Absolutely.

JESSE: [10:04] Yeah. So, tell me a little bit about getting into your MD Ph. D. program. It’s not — I think, as I mentioned before we got going, I don’t think I’ve talked to anybody else with an MD Ph.D., maybe one person that’s just not coming to mind. It seems like people often choose one route or the other. And it’s kind of specialized to do what you do. So, how do you end up in a place where you’re like, Okay, I want to do both because of my particular interests.

ROBERT: [10:42] Yeah, how I got there, there’s probably a pretty common story. And I hadn’t been exposed to much research, when I was younger, and I had been exposed to doctors and found — I thought, well, I’m really interested in biology and science, being a doctor makes sense to me. And so that was kind of my — that was my default pathway when I entered college. I thought I’m certainly going to be premed, I’m going to go to medical school.

And then I was very fortunate, one of the Princeton alumni gave me a summer internship in their lab at the hospital for special surgery in New York City. And that was my first real exposure to lab-based research. I’d taken courses and done a little bit of lab-based research and classes and such, and just really fell in love with research and kind of came back and talked to, I think, my college counselor. And she’s like, “There are these programs where you can do a dual degree.”

So, I guess it’s for people who really just can’t decide what they want to do. And I had no idea what I was getting myself into, right. So, here I am, I’m 20 years old. Like, yeah, that sounds great. I’m going to do this dual degree. So, I’m 20 years old. Little did I know that I wouldn’t get my first paying job until I was 37 years old, right, a real paying job, [inaudible 11:56] you get paid a little bit as a resident. So, it was a long course. But you know, it did actually seem attractive to me, all jokes aside, about being indecisive. But this idea of kind of doing an MD and a Ph.D., so that you can do patient-specific research that you could try to do research that was more medically relevant, right. So, all research is really important.

The people who discovered CRISPR at a very basic science level that was a phenomenal discovery, and the translation has come later. But I think I really enjoyed kind of being on the bubble, of seeing patients and doing research. And that’s how I came into it. I kind of started down one path, found out that I liked something else, and was lucky enough to realize that there were these programs out there to do both. And you’re right, they’re not very common. I think when I graduated from my MD Ph. D. program, it’s an NIH funded program. And I think there were only about 120 slots in the country spread across, like all of the medical schools. So, it’s not a common path that people take.

JESSE: [13:10] You know, the beginning of your story, talking about being 20 and just being like, “Okay, let’s do it.” It reminds me of like, this philosophy, I try to keep, though, I find as I get older, it’s a little harder. It’s almost like, being a little naive, can be beneficial. Because sometimes you’ll take on things that otherwise if you really understood the scope of, you’d be like, “That’s insane.” I’m not going to do that.

ROBERT: [13:39] Yeah, well it’s true. And you know, when I’m interviewing students for these programs, and they’re asking me, would you do it again, you kind of hesitate a little bit. I love what I do. It’s been a fantastic path. But man, if I knew what I knew now, you’re right. I’m glad I was naive because it was a long arduous path to get where I was — to I get where I am now. And I love what I do but, man if I’d know, I’m not sure I would have chosen exactly this path.

JESSE: [14:04] Yeah. But at the same time to think about it, you know, here you are on the other side of it. And the other question that comes to mind is well, okay, being naive is good. But if I wasn’t naive, and I did understand the scope of it, is it simply a matter of having more confidence in myself to be able to get through these tasks?

ROBERT: [14:28] Well, yeah, 20-year-olds, that’s one thing they probably have a lot of is confidence.

JESSE: Confidence. Yep, I’ll figure it out, no problem.

ROBERT: The imposter syndrome comes later. Right?

JESSE: [14:38] Right. Right. Have you dealt with that at all? I know I’ve had a number of guests — it reminds me all the way back to like, Episode Five. I’ve forgotten her name. But her episode title is about imposter syndrome. I know it hits a lot of people And now you’re kind of running your own show. Has that played into it? Have you experienced it?

ROBERT: [15:09] Yeah, I mean, I think those doubts, right, always come in at some point in your career, and I just try to squash them down and say, “Look I’ve — yeah, I may not know everything, but you know, I can learn new things, I’m in a new position now so I think it comes up with almost everyone. There are definitely times when I’ve felt that creeping up. But fortunately you just kind of push it down and say I’m qualified to do this. I’ve trained my whole life to think about these problems. And if I need to learn something new, I learn something new. And you know, I won’t be an imposter for long.

JESSE: [15:52] You know, I’m sure you’re aware of the Dunning Kruger effect, where it’s like, if you know a little bit about a subject that you just started, and you have all this confidence, you’re like, “Oh, I know, everything I need to know.” And then as you learn more, you have this idea about, oh, there’s so much I don’t know, and I know that I don’t know a ton. I try to like, think about that.

And I wonder if simply being cognizant of that helps that imposter syndrome at all just like knowing like, this is the default mode of how my brain is probably operating. I don’t know. I don’t know that I have a question. It’s just really a thought like, does that ever play in where it’s like, okay, I know, this is why my brain is operating this way. And then somehow you can circumvent it because you know, you’re operating that way, or are you still just stuck in this rabbit hole of no, I like, I don’t know what’s going on?

ROBERT: [16:48] Yeah, no, I think being self-aware of how that happens, like, whenever you kind of dig into a new problem, you’re like, “Oh, yeah. I’m gonna take on this new research project, it’s going to be fantastic. You know, and then you think to yourself, you know, I’ve done this before. It’s never as easy or as straightforward as you think it’s gonna be. You think about this, like, oh, if I do X, Y, and Z this will prove to be true. And this, whatever, you know, drug I’m testing or signaling pathway that I’m investigating in cancer cells, and I’ve done this enough times, it’s never that simple. So, knowing that in advance, I think helps you get through it.

JESSE: [17:27] I mean, it sounds just like having a little bit of experience gives you a little more perspective. I know I don’t do research, but just thinking about, like, businesses, or if I’m building a new business or trying something new, like we’re doing a kitchen remodel right now. So, any new kind of project, regardless of what it is, I always assume I’m going to screw something up. Like, that’s the only thing I’m entirely confident about is that I will screw something up. The rest of it. I hope it goes to plan. But I know at least one thing is not going to go to play in.

ROBERT: [18:07] Yeah, absolutely. I mean, you have to anticipate problems and road bumps along the way. And I think going into that with eyes wide open helps you not get frustrated.

JESSE: [18:20] Yeah. So, you made the switch from, I’ll say, like an academic research setting, that’s correct, to private industry. I assume that jump is not necessarily as straightforward as it might seem. Can you tell me a little bit about the decision to go that way? And then maybe some of the things that didn’t go quite as planned, like we were just talking about?

ROBERT: [18:51] I mean, for me, the decision — Well, first of all, it’s been a long time coming. And so, you know, when I transitioned from academic medicine and research to industry, I transitioned to a company that I actually helped co-found years earlier and had been consulting for, for quite some time. So, it was kind of a — it was a very slow process. It took about three years to happen. And getting comfortable around the idea and thinking about what I wanted to do.

You know, for me, one of the things that happened in academic medicine, I was pleasantly surprised to kind of achieve one of my goals. A, just to achieve the goal was very satisfying, but to do it probably earlier than I thought which was to take something that we had worked on in the lab and turn it into a real meaningful outcome for patients.

[19:46] And I think once I had done that, I wanted to challenge myself in new ways and perhaps do it even more. You know, I think realizing in the academic side that it might take a long time to do that again, or it may never happen again, but to try and apply what I learned in that process of taking a scientific discovery working on it, and getting it basically translated into a therapy for patients was extremely satisfying. But then I wanted more. And so I thought the best way to do that was on the industry side.

[20:21] And luckily, I had this vehicle, this company that we had started and was growing and has a great group of people that’s ever-expanding, it made the decision easier for me. What was challenging about the decision is that I was giving up seeing patients. And that has been a motivation and an inspiration. I treat cancer patients who, for the most part, have metastatic disease, which means that they’re sadly going to likely die from their cancer at some point.

The good news is we’ve been able to extend survival significantly, but it’s always hard leaving patients. And I’m so grateful that I have been able to take care of wonderful patients over the course of my career. And they’ll always serve as a motivation for what I do and in terms of drug development, and always keeping them as the kind of central focus of why I do what I do.

JESSE: [21:17] I gotta make a couple of notes or I’m gonna lose several of my thoughts here. So, as we — I mentioned kind of the credits for you at the beginning, your Ph.D. is immunology, but you don’t really do that anymore. Where, where was the switch since obviously, there was some — there had to be a point where you’re like, “Okay, I’m interested in this.” And then now you’re more oncology, cancer-focused. Does that come — I think you mentioned it, kind of thinking about coming back into the work you’re doing now. But how does that switch take place?

ROBERT: [22:05] Yeah, I’ve gotten — there’s that naivete when you pick your program, right. So, I was probably 23 when I decided that I’m going to do my Ph.D. in immunology and fascinating science and immunology. And just so critical now to so many fields, whether it’s COVID-19 vaccine research, or autoimmune diseases, and now cancer. And it’s such a beautifully intricate system, the human immune system, and I think that’s what drew me to it.

So, I, again, 23 picked that. But as I progressed, and I love doing the research in that area, as I kind of progressed through finishing medical school, I thought about my options for what I wanted to do as a doctor, like what type of patients I wanted to see, what I wanted to specialize in. You know, I was very uncertain what I wanted to do. I was pretty sure I wanted to do medicine, meaning, a medical doctor of some type, whether it was a pediatrician or a medicine doctor. I didn’t really want to be a surgeon.

[23:07] So, I went down that route and it was during residency that I was first exposed to oncology or cancer medicine. I really never had the exposure in medical school to a lot of cancer. And I had a phenomenal mentor early on in my internship my first year of residency, who really inspired me. He was also an MD Ph.D., so another physician-scientist. He also did lung cancer, and I credit him as the reason that I wanted to go into cancer. We had a month-long rotation in oncology and found him very inspirational. And the fact that he was managing both a research career and seeing patients. So, that’s when the switch occurred.

[23:53] And at that point, I really wasn’t doing a lot of research. So, you do more specialty training after internal medicine and oncology. And it was during those fellowship years in medical oncology that I did more laboratory work with a basic scientist who studies cancer cell signaling. And that’s where I kind of retrained, so to speak, my research focus and learn more about how cancer cell signaling works. And it’s a critical component to how we think about killing cancer cells selectively. And that’s when I made the switch.

[24:28] So, it was many years later, it was probably in my kind of, I guess, late 20s, early 30s, that I decided to make the switch, but I felt like, what more, for me, at least what more important problem is there than cancer, you know? It doesn’t take many patients to see wow, this is a huge area of unmet need. And I’ve been very fortunate to train and have the early part of my career in a time when there’s been just phenomenal advancements in cancer because of our understanding of the biology. So, it’s been a– I mean, there’s always more to do. I tell my patients like, it’s never enough. It’s never fast enough because, you know, patients are dying of this disease. But it’s what inspires me.

JESSE: [25:14] So, before I ask you more questions about your research, specifically, to make sure I’m on the right page, but also that you the listener is on the page with us, I want to get a couple of like, basic things out of the way that are probably supermundane for you. But first, cancer is not just one thing, right? Because I know, there’s this idea that it makes a good slogan, right? Like, let’s defeat cancer, but it’s not a single disease that causes problems.

ROBERT: [25:47] Absolutely. And that’s a really critical point. You know, I think Nixon started the war on cancer. And it was a great idea, right, let’s focus energy on this really horrible disease. But over the 40 years since he — 40 or 50 years since he’s declared the war on cancer, we’ve understood that it is a very heterogeneous disease. Not only are there different types of cancers that affect different organs; prostate, or breast cancer, or lung cancer or others. But even within those diseases, and I mostly specialized in lung cancer. It turns out that when we look at lung cancer at the genetic level, it’s probably 15 or 25, different genetic subtypes.

[26:31] And that actually learning that, although it’s frustrating, in a sense that you have to develop all these 20 different therapies for lung cancer, it’s actually what’s allowed us to make the advancements because now we understand the genetics and biology underlying the differences, and that has actually been what’s helped us understand how to better treat it. Because we did tend to approach it as a bit monolithic. You know, all lung cancer is the same, all breast cancer is the same. And the more that we understand the uniqueness of different types of cancers, and can determine that through various testing methods, the better we can actually treat the disease.

JESSE: [27:12] And then the other kind of basic thing for you to get — I’d like to get out of the way is regarding when we talk about, like chemotherapy, or that kind of medicine for trying to kill cancer cells. We’re not again, talking about one thing. It’s — I’ll call it a class, but I don’t necessarily mean that in the strict medical sense. So, I’ll let you explain a little bit more about why we lump everything in that term.

ROBERT: [27:44] Yeah. When I think about therapies for cancer, there’s many different types. But you know, broadly, surgery can be a therapy for cancer. Chemotherapy is, you know, dozens of different drugs that work through various mechanisms. I guess the basic way to explain chemotherapy is that chemotherapy tends to better kill rapidly dividing cells than normal cells. And that’s why we use it right. So, the problem with cancer is that they have uncontrolled growth, and a lot of chemotherapies take advantage of that and selectively killing them.

The problem with chemotherapy has historically been that it’s largely empiric. Meaning that we don’t really understand why some people respond and why some people don’t. And it’s hard to pre-select patients that are more likely to benefit from one chemotherapy than another. And so chemotherapy is — it’s a broad class of agents that generally fall under that paradigm.

[28:43] What I have focused my career on and where there’s been a lot of advancements is targeted therapy. Meaning that the mechanism is very well understood. And we’re often able to kind of genetically select patients that that therapy is going to work. Because it works on you know, one target, it works on one protein in the cell, one gene in the cell. And those tend to have fewer side effects because they’re so kind of precise.

In fact, precision medicine or precision oncology is a term that has become very fashionable, because these drugs are very precise. Now, the problem is they only work in a select number of patients. But because we can select them ahead of time, we can say okay, well, this drug because it works on this target, we’re only going to pick patients whose tumors have that target.

[29:29] And that’s actually again, what’s led to a lot of successes in cancer. And then another broad class of therapy is immunotherapy, activating the body’s own immune system to fight cancer cells. And so again, there are many different types of immune therapies and drugs that are being developed.

But as a class, the drugs tend not to work directly at killing cancer cells, they actually more facilitate your own body’s immune system to kill the cancer cells. And then there’s radiation therapy and lots of other things that are being developed. And subclasses of each of those classes. But luckily, all of these tools have their place in helping cancer patients.

JESSE: [30:15] So, thinking about, this is something that I tried to formulate in my brain and my friend who’s a physician had explained to me basically how chemotherapy works when my father was going through a round of chemo a little over a year ago, or his rounds.

So, if I get this wrong, please correct me at any time, because my memory is faulty and he only explained it to me once. But I think as you mentioned, so chemotherapy is trying to kill off faster growing cells. And if I remember correctly, it does that by largely trying to shut down that cell regeneration on a broad swath versus a targeted system.

So, it’s problematic in two senses. The one he had mentioned to me that slow growing cancers often are not resolved through that kind of therapy because the rate is so slow. But then also, you get side effects, because you’re taking out all kinds of cells, not just the cancer cells. So, that’s kind of where you come in, it seems like when you’re trying to target this specific mechanism is what’s causing this rapid growth or uncontrolled growth in that specific cell, right?

ROBERT: [31:26] Absolutely. And, yeah, everything that you said is very true. A lot of slow-growing tumors don’t respond as well to chemotherapy. One of the reasons you have side effects from chemotherapy is that unfortunately– well, fortunately, I guess there are some cells in your body that are continually regenerating cells and the GI tract cells and the bone marrow, so a lot of chemotherapy caused low blood counts, because those are constantly being produced, right? New red blood cells and white blood cells are always being produced. And the chemotherapies tend to disproportionately affect cells like that. We’re oversimplifying a bit [inaudible 32:11] that’s true.

[32:14] And with targeted therapies, with these precision medicines, sometimes the abnormality in the cancer cell isn’t really kind of a mechanism of, or a mechanism that’s used at all sometimes. And so some of these therapies have very few side effects. Because the abnormality in the cancer cell isn’t really found in adult human tissues anywhere. And so those are the best-case scenarios, because you’re really selectively killing the cancer cell and barely having any effects on other organs or tissues in the body. And that’s what we strive for. It’s sometimes not possible.

JESSE: [32:53] So, can you give me again, as you mentioned kind of like, oversimplifying things, but that’s probably better for me, at least because I’m in no sense of the word capable of talking about this on your level. Can you give a little bit deeper overview of that, how that targeted therapy works? Is it in that sense of that drug goes in targets that very specific cell, or is it a cell with a specific mechanism that’s happening? Or how does that work?

ROBERT: [33:30] Yeah. Maybe I’ll start with one that I’ve worked on. So, there’s a gene and a protein called ROS1, R-O-S 1. And it is activated, abnormally, kind of a genetic rearrangement, a type of mutation in cancer cells, and it’s not particularly common.

It’s about 1% of lung cancer, and it’s found in other cancers, too. And the way that this drug works, and this is true of a lot of other drugs and targets, is the drug actually, specifically only binds to that target, and it fits like a key in a lock. There are other kind of similar proteins on the broad scale, if you looked at like the crystal structure of these, they wouldn’t look all that different. But at the very fine molecular level that drug is just keyed, right so that it fits in a pocket in that and it only inhibits that target.

[34:29] And so, in theory, it goes into every cell in your body. But, fortunately, and I picked this example intentionally, ROS1 is a protein that, as far as we know, probably has almost no function in an adult. It maybe is important during embryonic development. But in an adult no one knows what it does. In fact, when you completely remove the gene from mice, the mice are almost perfectly normal.

So, cancer has found this gene that can support, you know, unchecked cell growth. But fortunately, it doesn’t do anything else. And so when we give that drug to patients, it goes all over the entire body, it goes into probably every cell in the body. But it only turns off that protein in the cancer cells, and it kills those cancer cells selectively. And that’s almost an ideal situation where the drug is so selective and doesn’t have any side effects.

[35:25] There are other drugs that we’ve — that the cancer community has developed that only bind to certain types of cells. Actually, this is where immunology and cancer also kind of crossed that a couple decades ago, people realized that you could engineer human antibodies, the things that we normally use to fight viruses and other infections, we can engineer them to bind only to specific cells. And so they’ve actually engineered a number of antibodies that are now approved for cancer and they can kill — They only bind to the outside of some abnormal cells.

And then people have actually even further combined that, so you can actually attach a chemotherapy drug to it to make it even more potent. And the antibodies themselves can have effects in terms of killing cancer cells. But if you attach a chemotherapy drug to it, then it kind of concentrates the chemotherapy into the cancer cells. So, there’s lots of kind of very clever ways to try and selectively kill cancer cells. That’s really the goal, killing these abnormal cells and leaving the normal ones alone, right. So, get rid of the cancer and try to cause as few off-targets kind of collateral damage to the patient as possible.

JESSE: [36:42] I mean, I would assume, like the example you gave when you’re taking the antibodies and attaching a chemotherapy drug to it to deliver to a targeted area. And just in general, with targeted therapies, are you seeing, because it’s targeted, because you’re not taking this kind of hack and slash, like, broad swath approach; do you end up with less negative side effects because of that?

ROBERT: [37:11] Yeah. I’d say in general, we are reducing side effects greatly for patients. I’d say there’s still a long way to go that almost all of these still have side effects. You know, some are better than others, far better than some of the chemotherapies that we’ve historically used. But it’s still a work in progress.

JESSE: [37:35] Yeah. I can’t recall exactly where through kind of looking through your research and stuff about you, I had seen something about cancers becoming resistant to certain therapies and you developing things to try to be more effective against those cancers. So, this is something I was really curious about. And again, you know, treat me as like a 100 level college student. But thinking about like — last week, I was speaking about antibiotics and being in a post-antibiotic world. And that makes sense to me that the mutations that occur, and then they become drug-resistant.

But then I think about cancer and at least in my head. I think, well, if Jeff has lung cancer, and I talked to him, like he’s not going to give me lung cancer. So, because I don’t see it as a contagion. I guess I fail to grasp how they become resistant to certain therapies. So, how does that situation occur?

ROBERT: [38:53] Yeah, actually, the antibiotics analogy is a very good one and one that we’ve turned to. And in fact, maybe HIV is perhaps like the best example of trying to understand drug resistance. And actually, some of the mechanisms are very analogous. So, I mentioned that lock and key analogy. And the way to think about it is that one type of resistance that crops up with almost all of these small molecule inhibitors, like the example I gave you of the ROS1 inhibitor, is that if you change the pocket that that drug binds to by just one nucleotide, so one genetic simple change, a C to G, an A to a T, that changes the amino acid and that changes the shape of the pocket.

And sometimes that change in the shape of the pocket allows the cancer cell to keep growing because it doesn’t affect the function of that protein, but that drug can no longer bind. And that’s exactly what happens in antibiotic resistance.

[39:56] And so, what we, you know, and again, at a molecular level, this is relatively easy to tease out so we can resequence the patient’s tumor and find, “Oh, well they got this mutation.” And now you can actually model what the picture looks like and the drug binding into the pocket. And you’re like, yeah, that spot has changed, the drug no longer fits. And that actually has led to new drugs being a slightly different fit that can overcome that resistance mutation.

And that has been a successful strategy for many different types of targeted therapies is they just keep, you know, it’s like a race between the cancer and the drug development companies and researchers to try and identify all the potential mutations and then find drugs that can fit it. That’s one type of resistance, that’s actually the easy type to overcome.

[40:48] One of the things we’ve also researched is, unfortunately, the cancer cell is a lot more complex than a bacteria is. The bacteria or virus often only has — virus sometimes only has eight or 10 genes, cancer cells have 20 or 30,000 genes to choose from. And so one of the things that cancer cells can do is say, okay, well, you’ve, you fit the key into the lock perfectly, you’ve shut down that protein.

But I’ve got these other hundreds of genes that I can now mutate and do the same type of thing. And that can be a little bit more insidious. And that’s where a lot of my research was trying to understand. We call that bypass signaling, right? So, the drug is effectively shut down the cancer-causing gene, but the cancer cell just turns on another one, instead, that can keep the cancer going.

[41:38] And unfortunately, when you have cancer, you have hundreds of millions of cancer cells, and a lot of this has already occurred, and that one just got lucky. It’s like kind of pulling the lever on the jackpot of, you know, the cancer cells are constantly mutating. That’s actually one of the problems of cancer is that it mutates almost every time it divides, it probably mutates, actually more than every time it divides. And so just by chance, there’s often a resistant cancer cell in there to the drug, even if it’s very effective. And so that’s the other type of resistance that we’ve spent a lot of time trying to catalogue.

[42:13] And the good news is, not to make this all grim, is that cancer cells often turned to kind of the same set of genes that they like to turn on to get around things. So, although there are a lot to choose from, it seems like at least in the area of research that I’m in, they tend to focus on maybe a dozen or so or a handful of pathways that they like to activate, so it’s not infinite, and it is achievable to figure this out and drug them all.

JESSE: [42:41] So, I think this — actually, you’ve already touched on and probably answered the question I was gonna ask is that so the mutation’s occurring like, potentially during therapy. Like a drug’s being delivered, may be targeted, but just by the nature of cancer and how fast it, you know, is creating new cells, you get that mutation. And then now you have to target that new mutation because of the lack of efficacy not fitting that key together anymore.

ROBERT: [43:16] Yeah, that’s exactly right. Yeah. And as I said, a lot of this is, unfortunately, predetermined that, when you start, the vast majority may be effectively killed by your drug. But just by chance, during the prior few months before you gave that drug, there was one cell out of 20 million that had just the right mutation, because again on a broad scale, if these cells are dividing all the time, the numbers work in the cancer’s favor of having made quite, quote, ‘the right mistake’ at one point in time.

JESSE: [43:51] So, the, if we try to make a pie in the sky kind of approach to what you’re doing, the idea is that you figure out enough therapies that regardless of what mutation cancer takes you’re like, “Okay, well, if green didn’t work, then we’ll use blue and blue didn’t work. So, it’s time for red, and just have enough options that there’s really nowhere for mutations to take a turn that you’re not unable to deal with.

ROBERT: [44:24] Yeah, absolutely. And that’s, I think, where maybe the HIV example comes in, right. So, right now we’ve been kind of doing A then B, then C. And that has worked pretty well. I think, where the future lies in cancer therapy is combining the right combinations of X, Y, and Z to begin with, so that the cancer doesn’t ever get the chance to develop that resistance.

And that’s really what happened in HIV. First, it was one drug, and that worked for a short time and then they added two and that worked a little bit better. And now that you have three it’s very hard, you know, you’re not necessarily eradicating the HIV, but it’s very hard when you have that selective pressure of three different drugs boxing the virus in that it’s very hard for it to mutate.

[45:12] And I think that’s the idea that we like to draw from in cancer as we think forward is, can we come up with a right two, three drug combination to really box the cancer cell in so that it can’t get out of that box, and it can’t mutate and still survive and become resistant? You know, it’s a lofty goal, but one that I think is one that we’re working towards.

JESSE: [45:35] So, does that become like a statistical probability question where, as you mentioned earlier that, okay, so there’s plenty of options for cancer to choose from, but it often goes to X, Y, and Z, I think you mentioned a dozen or so options. And the acronyms I think are listed on your website, and [inaudible 45:55] sent those over to me. So, that isn’t a matter when we just think of statistics say, well, if it starts with this particular protein, and it’s messing with that one, we know that 90% of the time, if there’s a mutation, it’s going to be this one. And is that how you come up with a combination?

ROBERT: [46:14] Yeah. And then I think we have to start challenging ourselves too. You know, that there are some kind of cancer cell nodes that are, you know, I talked about maybe a dozen genes. There are some that are, you focus down to like three or four, like critical nodes. And the problem is, those tend to have a lot more toxicity.

They tend to be a little bit more chemotherapy-like because people use them. And the question is, well, if you combine them in the right, just the right combination, maybe the patient’s, you know, get a lot more side effects for a short period of time. But if you can come up with the kind of right combinations, even if there’s more toxicity, can you not allow that — any way out for the cancer cell, right.

[47:00] So, eliminating the statistical probability of [inaudible 47:03] making it. So, it’s hard to imagine that a cancer cell could come up with the right three or four mutations at once to get out of that box. So, then that gets into your statistical probability, right? If you apply enough different selective pressures, statistically, the cancer cell might not be able to get out of those. But again, that’s more theoretical now.

JESSE: Right, right.

ROBERT: [47:29] There are some — I mean, there are some like pediatric cancers, where we give very intensive kind of sequential regimens where we hit the cancer so many different ways. And it’s a really tough course sometimes over one or two years that you do — are able to do that. And again, I think maybe we need to start thinking that way, again. I think the doctors in the 50s, and 60s, and 70s are sometimes willing to kind of push the limits more in terms of doing this and occasionally, you can cure patients with the right combination of drugs.

JESSE: [48:05] It’s interesting to hear about and like I said, I’m glad you came to talk, because you just — I think it’s something — Right now, everybody’s focused on COVID, and I think rightfully so. But even if we get — if or when we get to the point that that’s not the top thing on, like, the public’s consciousness, like, I think cancer consistently, all the types of cancer consistently stays as this kind of archenemy, so to speak of, like humanity, where it’s like how are we going to beat this thing?

So, just on a personal level, it’s interesting to hear the kind of stuff that you’re doing and trying to make it more precise, even if it’s a matter of like you mentioned I think with ROS1, you said, it was like 1%. Well, it’s still 1% of people that okay, you can get a targeted therapy. Now, let’s move on to the next percent. And maybe it takes a while, which it probably will. Anything like this does take a while, but I don’t know, it gives me some kind of hope. It’s always nice to feel a little hopeful that people are working on things like that.

ROBERT: [49:23] Yeah, and I think — I mean, going back to the COVID, you know, I think it just highlights the importance of medical research, the two vaccines the mRNA vaccines from Pfizer, and Moderna, you know, Moderna was working on mRNA vaccines for cancer research, right.

So, those actually, so again, the cross-pollination that happens I mean, it’s an amazing time to be in science and our understanding is so much greater and these things — I think it just highlights the importance of medical research because you know, had it not been perhaps for Moderna doing research in cancer vaccines with this mRNA technology, maybe we wouldn’t have a COVID vaccine right around the corner.

JESSE: [50:08] Yeah. It’s kind of a [inaudible 50:12] way to put it, but it’s like happy accidents. You know, what I mean? Like it wasn’t intended to be, but then you can see the crossover effect and go, “Oh, hey, maybe, let’s try this.” Robert, as we’re starting to wind down on time here, you’ll actually get to be the very last person this year that I ask this question to. I’m asking everybody this year, a single question that’s kind of pervasive across all athletic disciplines. So, I’d like your opinion on what do you think the purpose of sport is?

ROBERT: [50:47] It’s a great question. I — it’s so many things. I feel like it gives you, for me, I guess it gives me focus. And swimming is kind of a unique support. It’s very sensory deprived, right, especially the summer, I spent my time transitioning from a pool because the pools were all close to swimming, open water. So, my lap was now a kilometer. And so it’s very sensory deprived. And for me, I find that it allows me to kind of think and recenter and focus. You know, some people see it as a distraction. I think I, you know, it gives me an outlet to focus and unplug.

You know, especially, swimming as I said is very unique. I don’t — I can’t listen to music, I can’t talk to other people while I’m running side by side. You also learn how to become a very good 10-second conversationalist when you’re doing interval training in the pool. And you have conversations that like, broken up into very short pieces. But yeah, so for me, I think it’s about focus. And maybe that’s why I gravitated towards swimming is I like the kind of unplugging, the solitude, no phones, no music, no anything but me and my thoughts.

JESSE: [52:15] There is something nice about that and I actually find myself when I’m in the pool, you know, my eyes are open but if I’m really paying attention to what I’m doing, I’m not really seeing anymore. The lines there, I’m not really looking at it.

Sometimes I even like will close my eyes like [inaudible 52:38] in the pool. That’s more of a technique thing, just making sure both my eyes are coming up when I breathe. But it’s like, I’m not paying attention to the visual input so much as I am just like inside my own head, and how do I feel? And you can’t really do that with running, you definitely can’t do it cycling.

So, yeah, I think you’re definitely on to something there where it’s like, you can focus and let go of at least one of these senses that maybe several, we can’t really hear much either, and kind of zone in on just what you’re doing. So, I’m definitely with you there. Robert, if people want to catch up on your research, see what you’re posting on Twitter, where can they find you?

ROBERT: [53:31] So, I’m on Twitter and I’m on LinkedIn. My lab has a page on Facebook. So, I’m all over social media.

JESSE: And if you’re on the YouTube version, we’ll have Robert’s handle on the screen. Otherwise, we’ll try to keep it in the description so you can find him easily. Robert, thanks again for hanging out with me, telling me a little bit about what you do, give me a little hope for the future. That’s always nice to have, especially in times like this. So, I hope you have a great weekend and have a great ski trip.

ROBERT: All right. Thank you so much, Jesse. I appreciate you having me.

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