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June 3, 2022 by Ania Wronski 11 min read

The Hills and Valleys of Precision Medicine with Dr. Todd Druley

In the latest episode of On the Drop podcast, Mission Bio CMO Todd Druley, MD, PhD, discusses his career in pediatric oncology and molecular genetics, what drew him to Mission Bio, and how we’re utilizing the Tapestri platform to tackle some of the biggest challenges in precision medicine.

Ania Wronski: I’m Ania Wronski. I’m a Director of Market Development and Applications here at Mission Bio. Today, we’re talking to our Chief Medical Officer, Dr. Todd Druley. Welcome Todd!

Todd Druley: Thank you, Ania. It’s really nice to be here. I’m really excited to be part of this team.

Ania: That’s fantastic. And we’re really happy to have you. So, you have a really interesting background. Can you tell us a little bit about what you’ve done in your career?

Todd: Sure. I was always interested in genetics and interested in medicine. So I trained as a pediatric oncologist and I got my MD and my PhD at the University of Illinois in Chicago. From there, I went on to Washington University in St. Louis, Missouri and studied pediatrics. And so my PhD from Chicago was in molecular genetics and then I wanted to apply that to patient care.

What attracted me to Washington University was the fact that, at the time, they were doing about 20 to 25% of the human genome project, which was really cutting edge, this was 20 years ago. I wanted to be around that – that’s where genomics was happening. It was a pretty new field. So when I got there, I studied pediatrics and then did a post-doc and I chose to do a post-doc for a bioengineer – and so Rob Mitra was my mentor. He was a co-inventor of next generation sequencing (NGS) when he was a post-doc with George Church at Harvard. This was around the time when the human genome had been finished and at Washington University they’d sequenced the very first human cancer genome. So this is a 40-something woman with acute myeloid leukemia. And that was the first time an entire genome had been sequenced from a cancer patient. So that was really exciting and it made a big splash.

Our adult oncologist started to bring genomics into the clinical arena, but there was nobody at the time who was really doing this for the pediatric population. So, I guess I was lucky, but it really opened a door for me to create a niche as the liaison between the university’s really fantastic genomics enterprise and the pediatric subspecialties. And so created my own academic research and really enjoyed that. I had several students and post-docs there.

Ania: What drew you specifically to pediatric oncology?

Todd: Well, I think, when you think about those questions, these are conditions that nobody has done anything to bring them on. You know, we talk about adults that are smokers or whatever. There’s various things that happen. And I’m not blaming anybody, but it’s a much more of an environmental driven cause for adult cancers and in the children that just isn’t the case.

You know, conceptually, they haven’t even had enough cell divisions for a single cell to acquire enough mutations to become a cancer cell. So what’s going on, it’s just conceptually a very different problem and I’ve always found that very compelling.

Then clinically, there’s a tremendous amount of money and energy and effort put into adult cancers because there’s tens of thousands of people that are afflicted with this worldwide every year. But thankfully pediatric cancer’s essentially a rare disease, but that also means that there just isn’t the investment.

So the idea has always been that if we create something for adult cancers that will trickle down and help the children eventually, but the causes of these cancers are so different that what drives an adult cancer is not the same thing. And the cures are not the same thing.

“As a clinician, I’m finding myself, treating children with drugs that were developed in the ’70s and early ’80s, and they’re not getting the advantage of the targeted therapies that are coming out today. So being able to develop molecular diagnostics in that space, it felt to me, like a great way to help bring clinical care for children with cancer into the 21st century.”

Ania: Having worked in breast cancer for many years myself, it’s a similar story where there’s a lot of the genetics, a lot of the Cleveland clinical trials are not often done on women, especially pregnant women. And it’s very much the same issue where it doesn’t translate as well. The biology is different. And so it’s definitely a big issue. And obviously it’s harder to work on infants and kids because there’s more risk and they’re in such an early stage of life. So I appreciate the work.

Todd: Well, thank you very much. They’re very resilient. You know, I think the cure rates for children just in general are around 65 to 70%. So two out of every three kids that you meet are going to do okay. Now that’s mostly due to advances in surgery for brain tumors and chemotherapy for leukemia. The other cancers haven’t fared nearly as well, but these children take a tremendous hit because they’re growing, they’re developing. So there’s a lot more plasticity in their cells than what we have as grown adults. So pound for pound, they can actually take a higher dose per unit of weight of chemotherapy and continue to sort of grow around that injury, whereas adults can’t really do that. But it doesn’t mean that we understand why they got cancer and we don’t offer them a targeted way to avoid that excess damage, which I think is where we’re lacking.

Ania: Absolutely. I think it’s, given that our listeners may not necessarily be cancer researchers, we really still don’t really understand cancer, right? We understand a little bit more every day but there’s still so much we don’t know about it.

Todd: Well, and as technology has evolved, we keep seeing how much less we actually know about it. It’s not one disease, it’s a thousand diseases that all have 50 different causes and so it’s an enormous problem.

Ania: Absolutely. So what did you do next? Did you get away somewhere a little warmer than Chicago and St. Louis?

Todd: (laughs) No, I’m still in St. Louis, but through the work in my research lab, I was trying to develop a new diagnostic study for children with leukemia. And that introduced me to a company called ArcherDX probably around 2016, 2017. They had their own chemistry for finding fusions and structural lesions in a bulk assay. And so I brought that technology into our clinical trial.

Then in 2019, they asked me if I would be interested in becoming their first Chief Medical Officer, which I thought was either really brave or really stupid because I had no industry experience whatsoever. But they took a chance on me, and I stepped into that role and I loved it, had a great time, learned a lot about industry and how industry is really, I think, very dynamic at moving the needle for patient care. That was great experience, that company was acquired by Invitae.

“Through those efforts, there was a lot of work in bulk sequencing and circulating tumor DNA and really exciting stuff, but I got to see how eventually we’re going to plateau with what we can do with a single analyte or a bulk assay. You know, that to truly realize personalized medicine, it’s going to really get down to combining multiple measurements at a very, very high resolution platform. So that’s what’s brought me to Mission Bio and here I am.”

Ania: That’s a perfect segue to my next question, which was around why you joined Mission Bio and why you believe in what we’re doing?

Todd: Well, I mean, there’s a fundamental paradox here and it’s everybody likes the idea of personalized medicine and precision therapy. I used to talk to patients or their parents and just to kind of gauge where they’re at, you know, people hear a lot about this in the news media, from friends, or online, but what does “personalized therapy” mean?

So if you would talk to parents of a patient and say, “How do you feel if we treat your child with a personalized therapy?” You know, they almost always say, “Yeah, that sounds great. We’re really excited about that. That’s the future, and we really want to do that.” But then I said, “Well, let me frame it this way.”

“Let me order several different tests, and I’m going to assimilate that data based on my personal experience and talk to people around me, and then I’m going to recommend a path for your child that I’ve never done for any other child.” And then the answer starts to become, “Well, we’re not 100% down with that” Right?

So what is personalized therapy? Are you part of 10% of that patient population? 5%, 25%? So, the paradox comes as we start to do more and more specific therapy for smaller and smaller percentage of patients, the reason they’re less comfortable about it is because we don’t always have all the evidence that we need to say, “This is undoubtedly the right course of action for you or your family member,” so that requires a massive amount of data.

And then we’re realizing that we can’t just look at a single metric. We can’t only look at proteins or only look at DNA or only look at RNA. We do better when we combine multiple things. But that means that the subsets get smaller and smaller. So I think, in the era we’re at, the laboratories don’t have unlimited capacity to do every single test on every single patient. It just is impractical. Certainly in the United States, the payer system is not going to support that. And families can’t support that out of their own pocket.

It kind of leaves us saying, “Well, we want to give you the best that we possibly can, but we can only do so much.” And so that’s where sort of the gray zone lies, I think. And that’s where our job is to say, “How can we add resolution and clarity in this gray zone?” That’s not just really exciting science and, “Isn’t that really cool” but is going to help a doctor say, “Ah, now I understand, this is a better treatment if I want to see this patient overcome their cancer.” So I think that’s where we’re at.

Ania: It’s something that I don’t think, us on the research side, we really reconsider the appetite of the patients to even want the treatments or, where, as a field developing, it’s not something that generally we even contemplate. So it’s an interesting challenge.

Do you see any other kind of challenges in the field? We’ve seen a lot, the former FDA commissioner said that he’s concerned about solid gene therapy and the availability of that in an interview. What else do we have to overcome in precision medicine?

Todd: Well, I think you raised a great point. I don’t know that the regulatory infrastructure is anywhere near being able to move quickly enough to really regulate this space. You know, we want there to be regulation. We want things to be safe, we want them to be what we think they are, but at the same time we can’t wait three years for every single assay and every single drug to go through the official approval process.

So we’ve had the lab-developed test system in the U.S. and other parts of the world for a long time. You know, Europe is moving away from lab-developed tests (LDT) and really moving everything under an IVDR umbrella, which should standardize the regulations from one country to the next, but is that going to allow the technology and the therapies to reach patients in a timely fashion?

And that’s, I think what we’re unclear with. The FDA for a long time has wanted to, not block the LDT market, but I think have a better sense of how are these LDTs being ascertained and evaluated, and they just haven’t been able to move fast enough to keep up with it.

So that’s a huge hurdle and I think the pharmaceutical companies, on the other hand, they’re spending hundreds of millions, sometimes billions of dollars to develop new drugs, and then it turns out that drug may only be applicable to a subset of a general population: 5% of patients that have a particular type of cancer.

That’s okay, but they need the technology to identify, “This is the right patient and that’s the wrong patient” because if you don’t have the right technology, now that entire program fails because you were unable to specify which patient was appropriate at the outset.

You’re putting more and more money into smaller and smaller groups of patients, which isn’t a bad thing, but it makes it even more important for the technologies to identify the right patients. But the regulatory structure is struggling to understand how to approve these technologies.

Ania: I feel like it really hearkens back to where you started, really, with the whole genome cancer project, the sequencing projects that happened in the ’90s and the early 2000s, where there was so much data, there’s still so much data from those projects that haven’t been utilized just from a research perspective, let alone more on the development side. And I feel like we’re battling sometimes just this sea of data, and what do we do with it?

I think that it’s both from a patient and a research perspective of how does it combine together? And I think one of the beauties of the Tapestri platform that we have at Mission Bio is that you get the same data set from the same cell, which I think fundamentally is the way the fields are moving, right, with spatial technologies and others where you have a lot more contextual information in addition to the genetic information and the proteomic information, all at the same time. We’re kind of moving out of that bubble system of those assays that you mentioned.

Todd: Yeah, I agree. You know, if you look at a lot of these personalized therapies thus far, you see the fish plots or however the cells are being, or the cancer’s being demarcated, but it becomes a game of whack-a-mole where there’s, “I treated this mutation and then this one came up, and I treated this mutation and this one came up.” And a lot of times, you’ll see in a bulk data set, “Here’s a mutation at 3 or 4%, and here’s another mutation at 4 or 5%. They’re probably in the same cell. And so if I treat one, I’m essentially treating them both” but it turns out not to be accurate at all. They’re completely disparate clones or subclones. And by treating one, I’ve allowed the other one to continue to expand completely unhindered.

And now I have a different problem that requires a different therapy. I think people are now realizing that these are very important for outcome and disease biology, and wanting systems that can give them that kind of clarity at the beginning. So you see the entire profile, the entire tree of this cancer, rather than just doing it in this serial kind of one by one fashion and always chasing the next thing to come up. Our goals now are to say, “Can we actually improve somebody’s outcome because we were able to define all of these clones and subclones at the time of diagnosis or the time of relapse?” That hasn’t been proven yet, but we’re confident that by treating these different things in parallel, instead of in series, hopefully we can make a better outcome for these patients. And that’s what we’re excited to demonstrate.

Ania: Absolutely. So is there anything that Mission Bio is doing at the moment that kind of gets you really excited? What gets you out bed in the morning?

Todd: Well, I think when I look at this particular platform, the Tapestri, and I think about the arc of a cancer patient, you can see where the Tapestri platform can touch the patient’s journey through their cancer diagnosis and treatment at multiple different stages.

We can do the diagnostic profiling either from a blood cancer or solid tumor, really great high resolution data, on all the clones and subclones that are there at that particular time. The patient gets treated. And now we have MRD programs in heme, and pretty soon to follow there will be MRD programs in solid tumors, where now we can check and see, “Is there residual cells? And if there is, what are the proteins and what are the DNA mutations that have caused this subset of cells to escape the initial treatment?”

Ania: For our listeners who might not know, can you explain what “MRD” is?

Todd: Sure. People call it different things. It used to be minimal residual disease. Now people call it molecular residual disease or measurable residual disease. What you want to be able to do is identify if there’s any remaining cancer before the patient feels the effects of it, before there’s a tumor that needs to be cut out by a surgeon or there’s a blood cancer that’s invaded the bone marrow or something like that. We can detect this at very, very low amounts from blood or bone marrow or whatever specific body fluid or tissue we have to analyze. Then if the patient does relapse, they might go on to a clinical trial or get a cell and gene therapy.

Mission Bio has a really exciting and growing portfolio of quality control for different cell and gene therapy products with various different companies, trying different methods of engineering these products. So you can offer the clinician, we’re comparing apples to apples with how you’ve identified this recurrent disease in your patient with the therapy that they might be getting, whether it’s CAR-T or NK or a virus based measure. Then you get the disease back under control and you go back into monitoring for any residual disease again.

“The Tapestri platform can touch all these different points of the same patient’s arc giving different, highly granular data along the way, which that’s exciting to me. We’re doing these things right now in sort of different pieces of our profile, but eventually I see these things all overlapping and merging.”

Ania: It’s very exciting stuff. Well, I think that’s almost all the time that we have. I just wanted to ask one last question. What is your favorite ice cream flavor?

Todd: Oh, I’m chocolate all the way.

Ania: Just plain chocolate?

Todd: Can’t go wrong. If you want to put a little bit of peanut butter on top of it, even better, but just chocolate always wins.

Ania: Noted. We’ll keep that in mind for the next ice cream social!

Todd, thank you so much for joining us. Our next episode will focus in on one of the topics that Todd talked about, which is MRD, or Measurable Residual Disease, and how we’re using Tapestri to really be able to identify that earlier with much higher sensitivity. Join us next time!



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