Developing an early diagnostic test for bile duct cancer

In this episode of Making the Rounds, Jesse Kirkpatrick, a third-year medical student at Harvard Medical School talks about his research in developing an early diagnostic test for cholangiocarcinoma, a rare cancer. View his poster (PDF).

Learn more about the AMA Research Challenge.

Speakers

• Jesse Kirkpatrick, third-year medical student at Harvard Medical School
• Brendan Murphy, senior news writer, American Medical Association

Host

• Todd Unger, chief experience officer, American Medical Association

Listen on the go to the full episode on Apple Podcasts, Spotify or anywhere podcasts are available.

Unger: Welcome to Making the Rounds, a podcast by the American Medical Association. Today’s interview features one of the finalists for the AMA Research Challenge, which is the largest national research event of its kind. Join us for the main event in February where the five finalists will present their research and compete for a ten-thousand-dollar grand prize, sponsored by Laurel Road.  For the full details, visit ama-assn.org/finals. Here’s AMA Senior News Writer, Brendan Murphy.

Murphy: Hello and welcome to Making the Rounds, a podcast by the American Medical Association. I'm Brendan Murphy, senior news writer at the AMA. On this episode, we continue our series of interviews with AMA Research Challenge finalists. The top five research projects will compete in the finals event on February 6. Today I'm joined by Jesse Kirkpatrick, a third-year medical student at Harvard Medical School. Thanks for being on the show, Jesse. How are you?

Kirkpatrick: Doing great. Thanks for having me.

Murphy: We are very excited to have you and learn more about your project. Your submission to the AMA Research Challenge is entitled, “Detection of cholangiocarcinoma with protease activity probes.” Can you tell us a little bit about this topic, why it appealed to you and how you got involved in the AMA Research Challenge?

Kirkpatrick: Sure. So, cholangiocarcinoma is not a disease that a lot of people think about, and that's because in large part it's a rare disease, but the truth is that it is one of the deadliest cancers there is, with five-year survival rates of less than 10%, which is actually on par with pancreatic cancer, which is a disease that a lot of people know about. The reason that one of the main reasons that cholangiocarcinoma has such a poor survival rates is that the vast majority of tumors are detected at an advanced and incurable stage. And the reason for that is that the existing diagnostic methods are actually quite inadequate for early cancer detection. And this appealed to me specifically because I actually have a family member who has a disease of the bile ducts called primary sclerosingg cholangitis, which predisposes patients to cholangiocarcinoma. In fact, patients with PSC, this bile duct disease, have a 400-fold increased risk of cholangiocarcinoma. And so, I've seen firsthand the importance, first of all, of getting annual screening tests for cholangiocarcinoma in patients with this disease, but I've also seen how difficult it really is to detect early disease. And so, it's always exciting and makes us happy when the imaging tests come back clean. But in the back of my mind, I'm always thinking, well, I know that these tests are not actually very good at detecting early bile duct cancer. And so, what really inspired me was the idea of developing an earlier diagnostic test for cholangiocarcinoma.

Murphy: What were some of the challenges you encountered in doing this research?

Kirkpatrick: So I guess going back to the fact that this is a rare, a relatively rare cancer, even though it's a really important one, unlike other more common cancers like lung cancer or colon cancer, when I started doing this work, there was actually no, there was no mouse model for cholangiocarcinoma. So it was really six years between when I first had the idea of doing this work and actually getting to do my very first experiments. Before I was able to, yeah, so it took six years before I was able to start doing this work because in that interim, a mouse model was developed. And the mouse model that we've been using was developed by our collaborators at Beth Israel. And in fact, it's a mouse model of bile duct cancer that develops in mice that have liver disease that resembles primary sclerosing cholangitis, which did not exist at the time that I started this work. And then like other challenges with working on a rare disease.

It's been challenging to get human tissue samples to really validate our approach in human samples. And then of course, it's a rare disease. There's not a ton of funding for cholangiocarcinoma research. And we've been really fortunate in recent years, there have been large donations that have been made to the field of primary sclerosing cholangitis research, some of which we've been able to take advantage of for this work related to cholangiocarcinoma.

Murphy: So certainly, patience has been an asset for you. What advice would you offer medical students who are conducting research?

Kirkpatrick: I mean, I think specifically for conducting research related to diagnostics, it's important to think about first, is the information you would get from a diagnostic test actionable? It doesn't really help you if you're detecting, let's say, very early-stage prostate cancer, if that prostate cancer would not actually cause any harm to the patient. In that case, you'd really be, that's sort of this issue with overdiagnosis. You'd be diagnosing a disease that wouldn't actually have an impact on patient care. And in fact, that is a problem with prostate cancer is a lot of patients get diagnosed with early-stage disease that would not have actually progressed. These patients are subjected to really unnecessary biopsies and even resections in cases where that disease might not have ever progressed. And so, you have to think carefully about if you get information from this diagnostic, will it change the course of care? Will it improve outcomes? Will it increase survival or quality of life? And then I think another important question or another important consideration for diagnostic research is thinking specifically about the clinical scenario. So is this a screening test that you would apply to the general population? Is it a what we call like a high-risk test? In patients who are at high risk for a certain disease? Or is it like a confirmatory test, kind of a follow-up test in patients who have already had a positive result from a screening test?

Murphy: What role did mentors play in your research and what, in your opinion, makes a good research mentor?

Kirkpatrick: I guess I'll start with the second question first. I think a good mentor is somebody who has your best interests in mind. Research can be extremely competitive. There is this extreme pressure to publish, to bring in grants. And people who go into academia, they are very, very passionate about whatever it is that brought them into that field. And so, it is actually rare, I think, to find a mentor who can, while also making sure that their lab is being productive and they're competitive for grants and they're publishing, they're also thinking about, well, what are your goals? What are your career goals? What are the things that really motivate you? And then they act, they really make an effort to make sure that you are able to work on those things.

And so, I wanted to start with my answer to the second question first, because I think that my mentor is such an amazing example of somebody who really exemplifies that. So my mentor is Dr. Sangeeta Bhatia, who is a professor at MIT, who's done some really just incredible work in both liver tissue engineering as well as nanotechnology. And she certainly didn't have a passion for cholangiocarcinoma or primary sclerosing cholangitis when I joined the lab. She probably didn't know much about it at all, but she could see how important these diseases were to me because of my personal experience. And she took a chance on me and gave me the opportunity to use her lab and use the expertise of the people in the lab, and her own expertise and her own connections to allow me to pursue research in this actually quite rare disease. And I think that hopefully she would agree that the risk has paid off.

Murphy: What are the next steps in this work?

Kirkpatrick: So the main idea of the work is, as I mentioned, we need better earlier diagnostic methods for cholangiocarcinoma. In particular better methods to distinguish cholangiocarcinoma, this malignant disease, from benign underlying diseases like fibrosis or inflammation. So we developed a kind of a nanotechnology, a nanoprobe, that is able to detect a certain type of enzyme that is dysregulated in cancer. Cancer cells make these enzymes, which are called proteases, as you mentioned the title of my work.

These proteases play a role in really all the hallmarks of cancer, including angiogenesis, invasion, metastasis. What they do is they cut proteins. And so, you can imagine these proteases being helpful for cutting surrounding tissue and allowing tumor cells to spread and invade into blood vessels. We developed a probe that was able to detect these proteases and bind to and light up tumors. And what we've shown so far is that we can take these probes and we can administer them, we can take a fluorescent version of these probes, administer them into this mouse model of cholangiocarcinoma. And we see that this fluorescent probe is able to distinguish bile duct tumors from benign bile duct fibrosis. But right now, this is sort of a proof of concept because fluorescence isn't really something that you can use clinically, except for under certain circumstances.

And so, what we want to do is we want to adapt this fluorescent probe into a pet imaging probe. So, this would be kind of like a nuclear medicine diagnostic test where you take this probe, you conjugate it with some kind of a radio label, administer it into a patient who's suspected of having glandular carcinoma, and you can see does this radio label light up the suspicious bile duct lesion. And if it does, that would give you more confidence that this is indeed a malignant tumor. And so, we're working on adapting our existing probes into a PET imaging agent and performing preclinical testing using PET-CT in mice.

Murphy: How do you see this work impacting your career trajectory?

Kirkpatrick: I would say that this work is quite central to the clinical work that I want to do. I'm very interested in liver disease, in particular, cholestatic liver diseases like primary sclerosing cholangitis. And in these patients, there's no treatment. There's nothing that can really slow the progression of disease. The only thing we can really do is we can screen for cholangiocarcinoma. And if we find something, we can offer some kind of therapy, for example, resection or in more cases actually, liver transplantation for cholangiocarcinoma. And so, unfortunately, the minority of patients actually qualify for liver transplantation because the tumor extent is usually too advanced by the time the disease is reliably detected. So I think it would be incredibly validating to me to be able to actually see this technology through to clinical practice. I know that there are a lot of technologies that show success pre-clinically, but then don't end up actually making it to the clinic. This is something that I'm extremely committed to. And in my future career as a physician scientist, I will definitely continue to work on this question of early detection, whether it's this current technology or it's some future new and improved iteration of this work.

Murphy: What else should our listeners know about your journey in medicine?

Kirkpatrick: I would say I've had somewhat of a non-traditional path to medicine. I first got interested in medicine about 13 years ago when this member of my family was diagnosed with this rare and really devastating disease of the bile ducts. And I originally was and remain today extremely passionate about research because there are no effective therapies, and the outcomes really are not very good. And so, I was extremely passionate about research. And of course, the most direct path to doing research is to pursue a PhD. And when it came time, you know, I was at … that was coming to the end of my undergraduate years and I was asking myself, well, do I want to go directly into research and do a PhD or do I want to suffer through the long, arduous process of getting an MD-PhD, pursuing a residency, doing the fellowship, becoming a gastroenterologist, and ultimately, beginning to start my lab and start working on this research that's important to me. I couldn't stomach it at the time. I was young, I was more energetic than I am now at the age of 30. But ultimately, throughout my PhD, which I loved and I've learned so much and I wouldn't change anything about it. I did have the chance to do some clinical rotations that made me realize that I really did love medicine, and I wouldn't be fully satisfied if I didn't have one foot in the research world as well as one foot in the clinical world. And so that's been kind of my path and it's definitely different from the tradition.

I wouldn't necessarily recommend this path. There has been a lot of, I think the MD-PhD path is a well-trodden one that makes sense. The PhD-to-MD path is more difficult, more financially burdensome. But I do feel like throughout this process, I've really solidified these, you know, I've really solidified this passion for medicine. And this desire to do both.

Murphy: The AMA Research Challenge winner is awarded a $10,000 grand prize. What would you do with that money if you won?

Kirkpatrick: Wow, I mean, that would be pretty amazing. I wanna say that I would buy a car or do something, do something exciting with it or take a trip to Indonesia. I think that the reality is, and I'm sure this is what you'll hear from probably a lot of the people that you're speaking to, medical school is expensive. And like many med students, I will be graduating with a fair amount of debt. And I think that in particular, physician scientists do have this kind of trade-off that they need to make between expected salary and the amount of research they want to do. Most physician scientists are expected, if they're not full-time clinical, they're expected to make up some of their, or a fair portion of their salary through grants and other funding mechanisms. So having the opportunity to reduce my debt by $10,000 would really provide me a lot more freedom to focus on what really matters, which is being able to do the research that I need to do in addition to the clinical time that I want to have as part of my career.

Murphy: Thank you for joining us today and sharing your research and your journey in medicine with us today, Jesse.

Kirkpatrick: Thank you for having me. This was a good time.

Murphy: And our listeners, you won't want to miss Jesse and the four other finalists competing in the Research Challenge on February 6. Check out the description in this podcast for a link that offers more information on the Research Challenge. This has been Making the Rounds. I'm AMA Senior News Writer Brendan Murphy. Thanks for listening.

Kirkpatrick: Thank you.

Unger: Don’t forget to tune in to the AMA Research Challenge finals on February 6. Get the details at ama-assn.org/finals. Subscribe to Making the Rounds today. 

Disclaimer: The viewpoints expressed in this podcast are those of the participants and/or do not necessarily reflect the views and policies of the AMA.