Award-Winning Abstract From SIO 2023

An Interview With Christopher Malone, MD

This podcast episode is part of the SIO Corner, a collaboration between IO Learning and the Society of Interventional Oncology.  Today’s podcast features Dr AJ Gunn, SIO Publications Committee Vice Chair, and his guest, Dr. Christopher Malone, Assistant Professor of Radiology in the Interventional Radiology Section within Mallinckrodt Institute of Radiology at Washington University School of Medicine. They will discuss Dr. Malone’s Award-Winning abstract from SIO 2023, the process of actualizing this study, and what to expect from Dr. Malone and his colleagues at SIO 2024. 

This episode is also available on Spotify and Apple Podcasts!

Dr. AJ Gunn:    

We're really excited for this podcast to welcome Dr. Chris Malone from Washington University in St. Louis to discuss his award-winning abstract from the SIO annual meeting in 2023. But before we get going talking about your abstract, Chris, why don't you go ahead and just tell us a little about yourself and your practice?

Dr. Christopher Malone:    

Sure, yeah, thanks for having me. It's really an honor to be here. My name is Chris Malone. I am an interventional radiologist at WashU St. Louis. I've been here for almost 5 years. It's an academic practice, as you might assume. We're a very large transplant center. There's about 15 or 16 IR attendings, so there's a good opportunity for people to sub-specialize in their areas of interests. A lot of what I focus on is liver cancer, treatment of liver cancer—specifically HCC. Prior to Washington St. Louis, I did my fellowship at University of Washington in Seattle, which was also a busy Y-90 HCC program. And prior to that, I did my residency at University of California San Diego. So yeah, I've been all over the place.

Dr. AJ Gunn:    

Yeah, a little bit. So Midwest from two places on the West Coast. So, before we get started talking about your abstract, this was in the Basic Sciences Preclinical section for the abstracts. So it was essentially a translational science paper. Not a lot of IRs are doing translational research. So where did you first get your interest in translational research?

Dr. Christopher Malone:    

Yeah, so that's a great point. It's multipronged. I have a pretty extensive background in doing bench to bedside translational research prior to my IR career. I was in the T32 research residency track at UCSD doing molecular imaging research and, as I gravitated towards IR, I began to realize that as innovative of a specialty that we are, we still haven't answered a lot of fundamental questions about what our therapies do on a preclinical, basic science level.

And I think while we do constantly innovate, I think our impact could be a lot more by understanding that. And I think a lot of other fields are really good at that and I think they reap the gains from it, like medical oncology and radiation oncology have a good fundamental understanding. That's my motivation. I think it's also very rewarding, I think, if you're able to make a sort of bench to bedside observation or translation or some sort of discovery. So that's my main interest or motivation.

Dr. AJ Gunn:    

Yeah, I mean to me, I totally agree with you. I always think about interventional radiology, I use the term that we get distracted by new toys.

Dr. Christopher Malone:    

Yeah, absolutely.

Dr. AJ Gunn:    

Instead of driving down as medical oncology, you'll have a therapy and they have this network of hospitals to run a trial and in six months then they'll have 3000 patients who were in this trial. And what we end up getting distracted by is, hey, we found out about prostate embolization and obviously they've done a nice job in that space, but just as an example. Then instead of really drilling down why it works and comparing it to standard of care surgical therapies, we get distracted by, oh, the first 50 patients with a hundred micron beads, the first 50 patients with 30 micron beads.

Those are just easier publications to put out. So I think the road that you've chosen is hugely impactful for our specialty and so I really applaud you for that. I just want to ask you a little bit about the T32 program for people that are trainees or medical students that are listening in interventional radiology. So what is a T32 program? Do you think that that's essential for someone who wants to get into interventional radiology research, or what are the upsides and downsides? Could you talk about that for a second?

Dr. Christopher Malone:    

Yeah, sure. So a T32 is basically just the name of a type of NIH training grant. You could technically have a research track residency without it, but most places that do have it, do. That's how it's financially supported. I wouldn't say that you have to do that kind of track, but I didn't have a PhD, so I was more interested. I was interested in getting that extra research training. There aren't too many places that offer T32s in radiology or let alone interventional radiology, but they're out there. UCSD, where I trained, is obviously one. Here at WashU, we have one. I don't want to speak for other institutions, but there may be at least 3 or 4 other ones out there. And so what it does, it basically carves out time during your residency for you to do actual dedicated—usually, it's translational bench research. But yeah, I think a lot of that, you understand how the research game works, collaborate with people, which I think is most of the recipe for success.

Dr. AJ Gunn:    

Yeah, no, there's just so many things even in failures with research that you just learn along the way and how to write things and how to put things together. And there's a whole language to writing grants and things like that that is difficult to unlock, I would say, if you don't have experience in that sense. So, do you have lab space now at WashU? And if so, how did you get that set up? Was that part of the package for you to go there? Was that something that you negotiated when you started?

Dr. Christopher Malone:    

Great question. So I do have space. My pathway to getting lab space was admittedly a little circuitous and unique, but I'll try to take a stab at it. I was given a little bit of resources to do research coming into WashU, but what really set it off was I was introduced to one of the big scientists here, his name is Sam Achilefu. He has since gone on to UT Southwestern, but he operated a pretty big lab within radiology and he is a chemist that specializes in optical probes to diagnose and treat cancer, amongst other diseases. And so, I initially had some sit downs with him and he was telling me about some of his early work with radiopharmaceuticals and I really saw an opportunity how I could take that work and apply it to Y-90 specifically and tie it with my current practice of treating.

And so, he was gracious enough to actually give me a small little office in his lab. And so, I had enough resources to hire a research tech and, with some hard work, and there was some collaboration with other people in this lab, we were able to get some preliminary data and then, I was able to use that to apply for other grants, especially through RSNA and SIR. And with that support, I was able to carve out a little bit more of a footprint within the lab. He has since left, and so some of the leadership has changed a little bit within that research center, but through that, I was able to be like, "Okay, this is going to be my area," but there is the expectation for you to ultimately get NIH level funding. And that could be a whole other podcast in and of itself. And that's what we're working on right now to secure, which is no easy task by any means, but it's an interesting journey.

Dr. AJ Gunn:    

And honestly, compared to where most people get, you've made it so far down the road already in just a few short years. And so I think that's totally interesting and I think, as you know, it's a difficult road to travel and I think the fact that you were able, so fortuitous to find someone that had experience and provide you mentorship, and I really think inside institutions, things like that's super key for people, especially early on.

Dr. Christopher Malone:    

Absolutely. Yeah, it's critical. But I consider myself to be very lucky. Now the whole startup package thing, that's a whole other topic to discuss and-

Dr. AJ Gunn:    

Yeah, I'm not asking you to reveal internal negotiations.

Dr. Christopher Malone:    

Yeah, yeah. That's a unique conversation.

Dr. AJ Gunn:    

Well, okay, well, let's talk about your abstract from the annual meeting 2023. I'm sure you had many, but this one in the basic science categories, and for everybody that's listening, Chris and his team actually had the highest scored abstract in the basic science categories. So, why don't you go ahead and just give us the background on the project and where did you get the idea to start with this research project?

Dr. Christopher Malone:    

Sure, absolutely. So, some of the work that I was doing when Sam was still in the lab, we were basically doing in vitro experiments with Y-90 microspheres in different HCC cancer cell lines. So basically what that is, these are immortalized cancer cell lines, usually derived from patients decades prior, that are handed around worldwide. And we're basically seeing very different responses or behavior—biological behavior—to Y-90 between two different cell lines. And these two different cell lines were on the opposite ends of the spectrum in terms of their, I guess for lack of a better word, malignant potential. And so I was like, "Huh, that's really interesting." And I started looking into this more and it's like, well, HCC is a very diverse disease. It's very genetically heterogeneous, and by that, it means that different HCCs can express different proteins, they can express different RNA levels, they can express different, I guess, biology.

So when I'm looking back at the tumor board and I see the patient that responded really well to Y-90 and then the other one that just didn't, we always talk about, "Oh, that patient has bad biology," but well, what does that mean? What does that mean exactly?

Dr. AJ Gunn:    

Or it's the dosing, right? Or it's the first Y-90, it's the dosing wasn't hot enough, right?

Dr. Christopher Malone:    

Yeah, exactly. But I've seen patients that respond great to a lower dose and those that you blast them and they have an either slightly out of field or infield progression. And so that motivated me because it was a bedside observation that I also saw in the lab. And so I was basically another kind of fortunate meeting that I had, so as Sam was leaving, I met another now current mentor of mine. His name is Nick Davidson, and he's actually the chief of GI here at WashU. He's fantastic, and he has a preclinical interest in HCC.

We were talking about these issues and talking about basic animal models of HCC and how one of my pitfalls was, ‘how can I find something that is good that I can do liver-directed therapy on in an animal that is larger than a mouse?,’ because a mouse is incredibly difficult to catheterize. I don't know if anyone's really tried it, but smaller than a rabbit or a pig, because those models aren't very, I think well established, and they're large and they're expensive. And he's like, "Well, the rat’s just not that great," and we can go on to the nuances of that. And then, he brought up the topic of patient-derived tumoroids.

And so, tumoroids are basically tumor versions of organoids. And organoids are basically these patient-derived models that basically recapitulate the original organ or tumor, basically on a microscopic level, so in a dish. There's been a lot of prior work done on liver organoids or hepanoids, where you basically take patient liver tissue and then you can grow it in a dish under a very specialized media. And you can see these little tiny organs grow. And you can do a lot of functional characterization on them, but you can also do it with tumors. And that's attractive because they replicate the histological morphology of the original tumor, they replicate the genetic profile of the original tumor, all while you have concurrent clinical data from the patient. And so you can do a lot of things with these tumoroids. You can put them in an animal, you can make patient-derived xenografts, or you can just do basic fundamental experiments in the lab.

You can treat them with Y-90 microspheres, you can see how they respond. You can treat them with heat to simulate ablation. I thought that was a very attractive model to pursue. And one of the things that it really shores up on compared to cell culture work is that you had the concurrent clinical data, as I just mentioned. And so I know how this patient was staged. I know if they had gone concurrent Y-90 clinically, how did they do? Did they have a response? Was there a short term recurrence? And I can correlate that with what I'm seeing in the lab. The problem with cell culture work is that oftentimes the information on the patient where that came from is long lost, it's decades old. A lot of cell culture, the HTC cell lines are from hepatitis B-derived samples from Asia. And so to argue that there may not be certain biological relevances compared to our cohort that we see here in the West. And so, yeah, go on.

Dr. AJ Gunn:    

No, no, no, go ahead. Finish.

Dr. Christopher Malone:    

And so that's the main motivation to start doing this project, is to see if we can generate these patient-derived tumors in a dish, essentially.

Dr. AJ Gunn:    

Yeah. So tell me, help me understand a little bit better then, and the listeners too. Help me understand a little bit better about, how did you do this? Conceptually, I see what you're saying. I'm not saying I know how to do it, but conceptually what you're saying makes sense. But where did you get the samples from? Was it all biopsy samples or where did you get the samples from and how did you make the tumoroids?

Dr. Christopher Malone:    

Yeah, great question. We got the samples from basically any patient, and this was the part where I was basically scoping the board for a week or two out. Any patient that was going to get a standard of care biopsy, HCC was on a differential. The issue with that is we don't biopsy HCC.

Dr. AJ Gunn:    

Yeah. Not that often. Exactly.

Dr. Christopher Malone:    

And so, you really had to work hard to find these patients, but they're there. And then also, we've done a couple where we'll biopsy before we do a Y-90 mapping if we want to cinch the diagnosis of HCC, especially if their liver may not look too cirrhotic or nodular and they don't have a history of hepatitis C. And so I think we're going to see a lot more of those patients. I think they usually have some sort of non-alcoholic fatty liver disease component to it.

Dr. AJ Gunn:    

So from an IRB perspective, you weren't adding on biopsies just for, it was all people that were getting standard of care biopsies from the jump, correct?

Dr. Christopher Malone:    

Correct. But you have to discuss with them the fact that you're going to take extra tissue. So in addition to what's going to go to pathology, you're going to take extra tissue. I usually mention 2 to 3 extra cores. And then we also take, when indicated, some of the background's normal liver, and so that needs to be discussed in the IRB because there's theoretically an extra risk for bleeding. And so the whole IRB process actually worked out really well because there was already an IRB. There was an IRB through our GI colleagues, and we basically just added language to allow us to add on standard of care biopsies onto that in IR. And so it was much less painful than creating an IRB proposal from scratch.

Dr. AJ Gunn:    

Yeah, totally. So then what would you say, was the study just a proof of concept study that you create the tumoroids, or did you do tests on them or what happened after you had created the tumoroids?

Dr. Christopher Malone:    

Yeah, so both aspects. So prove the concept that we can do it, and then second, actually doing experiments on them. So I think what was demonstrated in the SIO abstract was that we established proof of concepts. This has actually been shown before. There's other groups, mainly in Europe. There's two papers out describing that they were able to generate these HCC tumoroids, but no one's done any experiments simulating liver-directed therapy on them. And so, the process is a little bit challenging, and then what I'll say is that we work very closely with one of the cores here in the GI section.

A core is basically a research entity that does certain work for a collaborator. And so we've been working closely with them, and they basically have been instrumental in generating these. And so we give them the tissue. My colleague, Naomi, she basically cultures them under very specialized conditions to try to get these tumoroids to come out and then grow. It's not always successful. And so preliminarily, less than half the patients that you get tumor tissue on will develop a tumoroid.

Dr. AJ Gunn:    

Really?

Dr. Christopher Malone:    

And a lot of that is based off usually the biology of the tumor.

Dr. AJ Gunn:    

Yeah. So-

Dr. Christopher Malone:    

Yeah, go on.

Dr. AJ Gunn:    

So one, from time to get tissue to the time that you have a functional tumor that you can do tests on, what's that timeframe?

Dr. Christopher Malone:    

Usually about 6 weeks, I would say.

Dr. AJ Gunn:    

Really?

Dr. Christopher Malone:    

Plus or minus.

Dr. AJ Gunn:    

And then, you might not know this, and this is totally fine. You know, you were mentioning earlier about bad biology and just tumors getting out of control and whatever else. So do you have any sense that people that have more aggressive tumors, like that tissue's better to make a tumoroid versus a less aggressive tumor? Or am I thinking about this the wrong way, or does it not matter?

Dr. Christopher Malone:    

No, you are, you're thinking about it totally correct. And that's a great question and observation. So you're right, usually the patients with either moderately differentiated or poorly differentiated are more likely to generate a tumoroid.

Dr. AJ Gunn:    

Interesting.

Dr. Christopher Malone:    

And that's also based on what's been published already by those European groups. And we've been seeing that preliminarily in our lab, although tentatively we've gotten one to grow from a more well differentiated one, but we still have to characterize that fully. So it's a downside in that you're not capturing some of those more indolent HCCs, but you could argue that the ones that you need to do the investigations on are the bad ones anyway.

Dr. AJ Gunn:    

Yeah, the non-responders, right?

Dr. Christopher Malone:    

Yeah, exactly.

Dr. AJ Gunn:    

What is it about the non-responders? And I'd love to hear your thought about this, but I'll just preface the question is like, well, I guess I'll just ask you, next steps, especially with these non responders, you could think about all sorts of things like what's their tumor microenvironment, what's their oxygenation levels, all these other kinds of questions that people have asked in cancer. Is that what you guys are going next with this as you're looking at it?

Dr. Christopher Malone:    

Yeah, I think one of the things we're looking at, we're doing a lot of genetic sequencing, both looking at specific mutations that we see in the tumoroid, but also gene expression levels and trying to see if certain genes are either up or down-regulated and whether these correlate with response to Y-90 in vitro. And also seeing whether there's any correlation to how they're doing clinically. It's a little bit of a challenge because not every patient will grow a tumoroid, and second, not every patient will undergo Y-90. But we've actually made some very interesting observations so far that I'm hoping to hopefully submit to an upcoming meeting eventually.

Dr. AJ Gunn:    

Are you able to share, it's fine if you're not. Are you able to share at all what you're looking forward to for SIO 2024 or submitting for that?

Dr. Christopher Malone:    

It's still a little bit preliminary.

Dr. AJ Gunn:    

Sure, got you. Yeah.

Dr. Christopher Malone:    

So maybe that's just me.

Dr. AJ Gunn:    

I won't put you out. That's totally fine.

Dr. Christopher Malone:    

Basically you have to, I like to replicate things before coming out with new data.

Dr. AJ Gunn:    

Yeah, yeah. No, I got you. Well, listen, congratulations on what you're doing in the project. Just in the time that I talked to you, the last 20-25 minutes, I've learned a lot about this and I didn't know anything about it before. And even me and my simple mind can see the potential applications for this. And so I just really congratulate you and am thankful for you and for your efforts, because I think this is the kind of stuff like you said earlier, is really the things, understanding mechanisms, at the end of the day, is the stuff that really pushes these oncologic treatments forward. And so appreciate your work.

Dr. Christopher Malone:    

Thank you. And I think also it elevates our fields, puts us on the same level as our other oncology colleagues.

Dr. AJ Gunn:    

Yeah, 100%. Because it's not just ‘does it work, it does work.’ And then those questions clinically is ‘does it work compared to standard of care treatment and why does it work and how can we maximize it and what are the problems there,’ which is exactly where you're starting to delve into. And so I feel like it's just a really exciting time, especially around HCC and Y-90 with all the new clinical data surrounding dosing and people trying to understand that better. And I think if people are attacking it from that way, and you're attacking it from, we have the therapy, how do we do better in patient selection, especially in our non-responders, right?

Dr. Christopher Malone:    

Yeah, exactly. 100%.

Dr. AJ Gunn:    

Yeah. Well, thank you for taking the time to speak with us and we're really looking forward to what you guys have next coming out of your lab at SIO 2024, which is going to be in Long Beach this year. And Chris, again, just thanks for taking the time to talk about this and for all the great work you're doing and hope to see more from your group.

Dr. Christopher Malone:    

Yeah, thanks for having me.

Dr. AJ Gunn:    

No problem.