September 19, 2018 / All Stories

Things That Make You Go Huh? Episode 5

In the fifth episode of our podcast, our clueless host gets schooled on … the complexity of researching medicines for childhood cancer.

Let’s face it: science can be hard.

Our host, Brett Hellman, former soap opera producer and current AbbVie employee, lacks any sort of scientific background and has recurring nightmares of his high school biology class. Now, he is tasked with talking to biopharmaceutical researchers about their work and translating it for the rest of us.

In each episode, Brett will explore some of the toughest and most relevant topics in medical science. This may be, at times, an exercise in frustration for the scientist being interviewed, but listeners will be rewarded with a new understanding not only of science, but about the scientific community at large – with all pretenses stripped down.

EPISODE #5

A Moving Target: The Complexity of Pediatric Cancer Research

Brett’s west coast road trip continues as he travels to Pharmacyclics, an AbbVie company, to speak with a pediatric oncologist turned researcher. While the topic is instantly sobering, Brett still has a multitude of questions: does cancer act differently in a growing body? Do children get cancer as often as adults? And, are the same treatments used no matter how old the patient?

In our fifth episode, Lori Styles, senior medical director, clinical science, Pharmacyclics, helps Brett understand how cancer affects children and how researchers are trying to beat this terrible disease at its own game.

Bio:

Lori Styles, M.D., is a senior medical director, clinical science, at Pharmacyclics, an AbbVie company. She is the clinical lead for the graft-versus-host disease (GVHD) and pediatric programs at Pharmacyclics and is the medical monitor for first-line chronic lymphocytic leukemia treatment studies. Styles has a medical degree from the University of California, San Diego, Medical School and completed her pediatric internship, residency and hematology/oncology fellowship at UCSF Benioff Children’s Hospital Oakland, where she practiced for more than 20 years.

Brett Hellman: Did you ever wonder … does cancer act differently in a growing body? How often does cancer occur in children? And does it happen as often as it does in adults? And, are the same treatments used no matter how old the patient is? Find out the answers to this and more on Things That Make You Go Huh?
 
‘THINGS THAT MAKE YOU GO HUH?’ INTRO MUSIC PLAYS

Brett: Hello, everyone ... it’s your science-challenged host Brett Hellman, and I’m STILL coming to you live today from sunny California. Our Things That Make You Go Huh? road trip continues as we pick the brains of more of our AbbVie west coast colleagues.
 
Normally I’d find some creative way to introduce our topic, but today’s subject matter really doesn’t lend itself to humor. We had the opportunity to talk to someone who has particular expertise in pediatric oncology. And while this isn’t something anyone wants to think about, the truth is I’ve often wondered … well, really anytime I’ve heard of a child getting sick, I immediately think about what can be done to make them better. So let’s just get to it – my producer Suzanne and I are here today with a very special guest to shed some light on this very important topic.
 
Lastly, just as a reminder, we didn’t have our normal audio guy with us on our road trip, and I was responsible for recording this myself … so please excuse any issues in sound quality.
 
So with that, let’s introduce our guest today … Lori Styles. Lori, can you tell us who you are and what you do?
 
Lori Styles: I’m Lori Styles and I am a senior medical director with Pharmacyclics in Sunnyvale. I am the graft versus host disease clinical development lead as well as the lead for pediatric development at Pharmacyclics.
 
Brett: Perfect. Great, we’ll get right to it. So I think our first question today is how are cancers different in children than they are in adults?
 
Lori: Well, there’s overlap, for one, but in general pediatric cancers are biologically different. They are often much more aggressive and assertive in a slow fashion — rather in a fast way. And then adult cancers are often slower or more chronic, such as chronic lymphocytic leukemia versus acute leukemia in children. Although acute leukemia can occur in adults as well … but just in general, the biology seems to be different with pediatric cancers, in general being more aggressive.
 
Suzanne Barston: Do we know why that is?
 
Lori: I think it’s driven by the biology. And you know, there are genetic influences on both adult cancers and pediatric cancers. But they just —though there might be acute leukemia in children and acute leukemia in adults, how they respond to therapies and the genetics that underlie them, often are different. So it’s really sort of, I think, biologically driven.

Suzanne: Interesting. So there are cancers that I’ve heard of that are like specifically childhood cancers, correct?
 
Lori: Yes. There are some cancers that occur predominantly in children. And then some cancers that occur in adults that, that don’t occur in children. Again, as chronic lymphocytic leukemia, CLL, doesn’t occur in children.

Brett: Do cancers present themselves differently in children than they do in adults? If it’s like pancreatic cancer or a specific type of cancer? Does it look different in a child than it does in an adult?

Lori: It can. And it depends on the type of cancer. For one, pancreatic cancer is extraordinarily rare in children. Or even, you know, sort of late adolescents. And it really depends on the cancer. You know, blood cancers might present similarly between adults and children, but the solid tumors, like pancreatic cancer, there’s not a real equivalent in children. So it wouldn’t obviously be expected to present in the same way. But it really depends on the cancer.

Suzanne: Does cancer act differently in a growing body? I would think, you know, adults are kind of … and I know cells are always changing. But adults are kind of done deals, right? But kids are growing and there’s just bones growing and cells dividing, right? So does it … does that impact how the cancer acts?

Lori: Um, not so much. And we’ll say there are cancers, something like hepatoblastoma which only really occurs in a growing -- in a very, very young child, usually under 2 or 3. That would, you know, only really occur in children and is probably reflective of the fact that that child’s liver and body is growing. I think where most of the concerns with cancer in children come is in the impact of the therapy, right? So in general, I would say children tolerate chemotherapy better. They are healthier, they don’t have decades of hard living or just, you know, wear and tear on the body. But they -- but we do worry about the impact of the therapies on a developing body. So it’s not so much the cancer itself but how we go about treating it, and its impact on the developing body. For example, something that would be expected to impact bone growth or organs that effect endocrine function, hormonal function, those would have a particularly deleterious effect on a child simply because they need those … those hormones to become, to fully mature. So it’s interrupting growth, interrupting development, or having irreversible effects on those systems, that I think is probably the most relevant in terms of treating and cancer’s impact on children.

Brett: Can the same treatments be used in children, as in adults?

Lori: There’s a lot of overlap between the, you know, the medicines, the chemotherapies, or now the targeted agents, in pediatric and adult cancers. They … it’s possible that a drug will work in both manifestations. Let’s say lymphoma. Lymphoma occurs in children and lymphoma occurs in adults. The types of lymphoma are different. In general, there’s some overlap obviously. So one might use the same quote, you know, lymphomatous drugs, drugs to treat lymphoma in an adult and children. How well they work might differ though between the two. So the same therapies are used, but often in different combinations, different doses, and they take different approaches. One, toxicity, as I’ve said, children often will tolerate a higher relative dose of a drug, than an adult. Just as an older adult, compared to a younger adult, doesn’t tolerate chemotherapy, so they can get a different dose. And so that can … that can impact things as well.

Suzanne: So you started out as a clinician, correct?

Lori: Yes, I was a pediatric hematologist oncologist.

Suzanne: Where did you practice?

Lori: Prior to coming to Pharmacyclics, I was a pediatric hematologist at Children’s Hospital in Oakland. And I think that’s had a … you know … a major impact on me as an individual and in my role here at Pharmacyclics. Children’s Hospital Oakland is an institution that treats children from all ways of life and is an incredibly diverse population and I was able to essentially, I was exposed to how disease impacts families in different ways. And what the … how that manifests for them. So that in coming to Pharmacyclics, I have that. I have that information and I have that experience that I can then share with the team here in terms of guiding us on what we do and in trying to impact, you know, the experience of having a child with cancer and how to really make that better and to have a positive impact on these families.

Suzanne: I think that’s a real interesting point, actually. Because I would think that when you’re developing, when you are doing science, right? And you’re developing medications. I mean, on one level it’s going to be about what’s in that petri dish or on that computer or whatever it is. But we also have to think really holistically about how that medication is going to interact in the real world, right?

Lori: Yeah. And I agree with that completely. Because, you know, even in just terms of just designing a study, you have to keep in mind, you know, what is real world? Right? So you can develop a drug for a set of conditions, but if that doesn’t occur in the real world, then it has no applicability for these people. So you have to develop what I would consider a clinically relevant study. Because even if it’s successful, if it’s not clinically relevant, then you’ve done nothing, really, to help the patient, or you’ve done little to help really the patient and the family and what they’re experiencing.

Suzanne: So what made you decide to go into research instead?

Lori: Well, as a clinical pediatric hematologist oncologist …

Brett: That’s a lot of words.

Lori: Yes, it is. Here in California, I actually did do clinical research … translational and clinical research. So I had a fair amount of research experience in drug development in the context of my clinical career. So the reason I moved was that I had a good experience with another pharmaceutical company and really saw that … was really attracted to the focus and the attention and the effort put into the rapid development of therapies for not just children. And I really felt like when efforts were focused, things got done and got done quicker. And time is an important element for patients, right? And in particular children. If you wait until you’ve done a definitive study, the longer it takes, the more time it means that there are children that have this condition and aren’t treated. And that can be a matter of life and death for them. So in essence, I was encouraged and intrigued by the concept of being able to do things, do them well and rigorously, and do them quickly.

Suzanne: So on that note, what is drug development like for children versus adults. I mean I would assume it’s the same, right, in terms of having the FDA approvals and enough clinical research.

Lori: It’s actually quite different …

Suzanne: Really?

Lori: And it’s really related to the fact that, if we want to speak specifically about oncology, because there are conditions that affect children equally, such as infections, as adults. But if you are speaking about oncology, it’s different simply because oncologic or cancer in children is a rare disease. Every single type of cancer in children would meet the criteria for a rare disease in this country. That makes it difficult, simply one to do a study. You know, you can’t do a 2,000 patient study. Or it’s very difficult to do a 2,000 patient study in a particular type of pediatric cancer, simply because it would take you -- could take you years to accrue that number of patients. And as I’ve said, that’s years spent where then children potentially wouldn’t have access to something that could be very, very efficacious. So the sort of burden of proof and the studies necessary for pediatric approval are different than in adults. And in general, you have to show a benefit. In a disease that occurs in both or has similarities in both, you have to show that there has been some evidence of benefit in an adult counterpart to that disease. Now there are diseases that only occur in children, so you would never be able to do that. There are a limited number of patients. So it’s not really a matter of how much energy you put into it, it’s just those patients don’t exist. Overall, I’d say that pediatric development is really quite different than an adult, and the considerations that go into are very, very different.

Suzanne: I feel like I hear about childhood leukemia more than any other kind of childhood cancer. Is that just perception or is that a cancer that happens more often?

Lori: That is the … that and brain tumors are the most common pediatric malignancies.

Suzannee: Do we know why? Is there a reason that blood cancer and brain cancer are more …

Lori: I’m probably knowledgeable to know why. I mean, leukemias are also very, very common in adults.

Suzanne: Right.

Lori: You know, probably not as much as some of the solid tumors like breast cancer or lung cancer. And I don’t honestly know the numbers. But I think, again, a lot of the solid tumors are due to sort of lifelong or decades long exposure to things. So they have a different sort of ideology. I think it makes sense that if someone has a genetic predisposition to something, that a leukemia would be the place where that happens because of, you know, it’s an origin in the actual stem cells of, of the hematologic system. But, I mean, I don’t know that anyone knows, you know, in particular why. But as I mentioned, hepatoblastoma is also a hepatoblast is sort of like, the stem cell of the hepatic cells. So it’s in those early cells. So if a person is going to develop a cancer or malignancy in childhood, it will often come from those … those early cells.

TRANSITION MUSIC

Suzanne: So Brett, I feel like I’m monopolizing this conversation.

Brett: I’m just trying to absorb it all. It’s a lot of information. I’m sure it’s a struggle on your end, but it’s, it was a struggle for me just to understand all of it.

Lori: Well, you make a very good point. And you’re not alone. It is a very complex area and so … but I think it’s important to convey the message that the development in pediatrics is very different than it is in adults. And it’s very complex. I, you know, lead the pediatric program here at Pharmacyclics, but I think I can honestly say that a lot of my colleagues here, even in clinical development, don’t have the same level of understanding that you have. That don’t understand, really, the complexity of pediatric development and what’s been put into place. To both promote pediatric research, but also to keep patients safe.

Brett: I think the other thing to me that was surprising was that any diseases in kids are considered rare diseases? And that if you …

Suzanne: Just for oncology.

Brett: Just for oncology, I’m sorry. So if you need to do clinical trials you can’t find enough kids necessarily, to do those clinical trials. So I think that was kind of eye opening for me as well.

Lori: Yeah, so I think you make an important point about the rarity. It’s obviously, as I’ve said, all the oncologic conditions are rare. And that makes it really hard to do the research. Not only just in terms of finding the patients having an adequate number of patients to sort of ask a test. You know, normally we have a very rigorous statistical evaluation of things. That’s often not possible. You don’t have the numbers necessary and it wouldn’t be possible to accumulate that number of patients. It gets further complex, now in the age of targeted agents and molecularly directed therapies, in that you might have more than one drug -- either in the same class or from a different angle, addressing the same disease. So then you have multiple drugs being targeted for the same condition. So then you’re not only just trying to find the patients, but you’re competing with someone else to actually investigate your agent. So numerically, it’s a challenge just to even do the study.

Brett: So my question is how do you move forward then? In that type of situation where you don’t have enough patients, you have multiple drugs, right, so … ?

Lori: Well, often, if it’s a really rare condition, we don’t. Let’s say it doesn’t occur in children under 1, you know, or under 2 or under 5. They won’t make you do that kind of work in those patients simply because they realize it’s so rare. And you know, there are other conditions though that if you want to, what you do is you have to design a study that is rigorous and will give you, you know, confidence that this can be used. But again, this is where the clinicians are left that in that intervening period, you know, what do you do? Because those studies, that data may never come through. And so it is really hard. You know, and just as example, it’s not even just efficacy. We’re talking about pharmacokinetics, which is dosing. How do we know how to dose? Can you just take an average 80 kilogram person and then when you give it to a 20 kilogram child, cut the dose in a quarter? Doesn’t usually work that way.

Suzanne: So that’s interesting. That goes back to that whole concept of, you know, back in the day they used to, before medical science evolved, we considered children like tiny adults, right? There was this whole thing, I remember reading, in like the 17th century, where they would -- that is what they thought kids were, little miniature adults. So that kind of speaks to that point of they’re not, right? It’s not just a weight. So let’s say you have an 80 pound adult female, which you know, there are some. Not me, but there are some. And then you have an 80 pound 10-year-old boy. Those are two … those are still two very different bodies, right, in terms of how drugs are going to interact?

Lori: Well, they can be. They might not be, but they can be. And you know, I have to say that clinical pharmacology people have you know, come a long way in being able to predict will an 80 pound boy and an 80 pound 90-year-old respond the same way? There’s a lot of changes in the maturity of enzymes and in the liver, or even in how we process these medications. So it really depends on the drug. And it’s not so much a 10-year-old, because I think … well, most 12 and ups, those probably are small adults.

Suzanne: Even … even for reproductive reasons? I would think cause the puberty people are …

Lori: Well, we have … we have lots of safeguards in place for reproduction in even adults. But I guess my point is the difference between a 12-year-old and an 18-year-old is probably not a lot. There’s some body weight, body weight differences. Some, you know, a girl wouldn’t have been expected, or a boy, to have fully matured at that point in terms of body weight and muscle mass. But in terms of the enzymes that are needed to break down the drug that result in a particular exposure. Those might be fully mature. Some of these … some drugs are metabolized by enzymes that are mature after a year of age. So it’s really complex, and as I’ve said, I think that’s where clinical pharmacology has helped us a lot in trying to predict these things. And when you design a study looking to see what dose should I give children, you always err on the safety. Because though it’s not common, there’s always the potential for a child to have a toxicity that you don’t see in adults … something … and this has happened with other drugs. But in a child, if you gave them something that then you could leave them with an irreversible problem or toxicity.

Brett: I think you bring up a good point. Which is that, you know, in children, they are growing so quickly, as opposed to older in life. So it’s kind of like a moving target, right? So when you’re putting drugs into a body that is developing so quickly. I don’t know if this is kind of a dumb question or not, but doesn’t that make it a little bit more complex too? To create drugs for children as well?

Lori: Absolutely. We have a particular focus on growth and development. So that would be growth, muscle, bone. And then, you know, hormonal, right? Because that’s the big change that is going on in puberty is, you know, full sexual maturation. So you don’t want to do something in that period of time where … where you would potentially hurt them for the long term. I will say that in pediatrics, that we have a lot of effective therapies in cancer, right? We do, we do … we actually do much better in children, in terms of curing cancer, than we do in adults. And so a focus and something that is always in study design, is how to minimize toxicity. Because this isn’t a 60 year old who is going to have a problem for maybe 20 more years. This is a 10 year old who may have to have a bad hip from avascular necrosis for 70 years. And the impact of that is not just on having a bad hip, but in gaining employment and being active. So the implications of toxicities in children are so … have so many more years to impact over. So it’s … we’re always balancing toxicity with, with sort of, with cure, because in pediatrics we’re always going for a cure. Control is not sort of our usual goal. But, so we have to balance reaching a cure, but at what expense? And that’s where I think that pediatric cancer has made a lot of progress. And we design studies to minimize toxicity and maintain … so if we have some diseases where we do very well, if we can minimize toxicity, but keep the same success rate, then that … that’s an important accomplishment. So I think -- but your point about it’s growth and development, it’s a moving target. You don’t always know what’s going to happen. So it has to be … in drug development for pediatrics, in pharmacokinetics or developing the right dose, and looking at toxicity, are really the really important things. Obviously efficacy is important, but one can’t count out that toxicity side of things.

Brett: So my next question is more on a personal level. So I mean I think any type of disease in any, at any age, is upsetting and can be hard to take. But I think in kids it seems particularly more heart wrenching. So I’m just curious: what inspires you to come to work every day and do what you do?

Lori: That’s, you know, an issue that gets brought up to me all the time. “Oh, I could never do what you do, seeing those kids with cancer or sickle cell disease” or any of these diseases. I guess it’s the thought that this is going to happen whether I’m here or not and my desire to do what I can to make the patient and the family -- do not discount the impact of disease on the family -- anything I can do to make that… that condition better and to have the family and the child be more successful. And that’s what drives me. And I actually feel -- I am inspired by the patients and their families themselves. They are amazing. And often it’s the people with the least, I mean in terms of economics or, you know, cultural, the people that are the most down trodden and have the very least, in order to do, that actually accomplish the most for their child. So you know, the families that are just barely making it by. I’m tearing up now just because it is …

Brett: So sweet …

Lori: It is what drives most people in pediatric hematology oncology. But I view being able to take care of these children and try to do something for them and their families as a real gift. And I’m really grateful for the opportunity to be able to do that.

Brett: They are lucky to have you … that’s awesome. Is this what you wanted to be when you were a kid? I always like to ask that question. What did you want to be when you were a kid?

Lori: Well, interestingly, I wanted to be a veterinarian. But I made the decision that I couldn’t, not to do that, because I couldn’t stand the sight of blood. I’ve always found it quite … I don’t know if it’s ironic or because I never use that word correctly. That I ended up in pediatric hematology oncology. But where all I deal with is blood. But I think that that first career choice of a veterinarian reflects my desire to help others, be that human or an animal.

Brett: That’s cool.

Suzanne: So does that make it hard then to use CAR-T on someone who has just had chemo?

Diane: So from the beginning of your career till now and looking forward, how have things changed in terms of your hope for the future?

Lori: I guess people always, you know, people say, “When are we going to cure cancer?” And I … to me that was always kind of a silly question. It would be like saying, “How are we going to cure disease?” Because it’s such a broad group of diseases. And I guess I’ve always viewed cancer as something … as the potential rather than this cure for cancer, is a control for cancer. Of how to, to restore normalcy. Because cancer is just really something turning itself on and never turning itself off and not ever following the natural progression of life and death of a cell. So I’m really encouraged and excited by the fact that we now know so much more about what drives cells, what drives the immune system, that we can go in there and sort of tinker with the machinery, if you will, to fix things and to get them back to a more normal function. As opposed to, in the past, just going in and if you will hitting that cell on the head with a hammer. And so that to me is a much more eloquent scientifically and biologically way of approaching disease in general, but in particular, cancer.

TRANSITION MUSIC

Suzanne: Thank you so much, Lori.

Brett: Yes, thank you so much.

Suzanne: This was great and I personally understood all of it. What about you, Brett?

Brett: I feel so much smarter right now.

Suzanne: I’m sure you are. So what did you learn today?

Brett: Oh, I learned … well one of the interesting things I learned I think was that in oncology at least, that most diseases for kids are considered rare diseases? Is that correct?

Lori: That’s right. Pediatric cancers are rare.

Brett: Also, that drug development in pediatric oncology is quite complex. It involves a lot more regulation and things that I never even kind of considered.

Suzanne: Like clinical trials and finding the patients, right? That was really eye opening for me. That you can’t necessarily find enough patients to get the results that you need.

Lori: And to answer the questions, most importantly.

Brett/Suzanne: Yeah, that’s right.

Brett: Interesting. I think lastly I think one of the things I learned and thought was eye opening was just kind of the potential side effects for these kids, only because in treating them, you have to think about kind of the long term effects for them, 70-80 years down the line. So that was definitely insightful for me as well.

Lori: Yeah, you know, I think that’s a really important thing that you’ve recognized because, you know, you didn’t understand that the toxicity and the long term quality of life is part of the equation. And that’s something we actually have to discuss with families. And discuss even amongst ourselves when we’re deciding on a course of action. Obviously everyone wants to go in, hit this thing hard, and get rid of it. But that’s not necessarily always the right choice. If you keep in mind what the long term quality of life for a sub-patient who is going to live potentially 70 or 80 years. So it’s a consideration in everything we do and we design trials actually even, to try to minimize toxicity and yet maintain the same efficacy. So efficacy is obviously the primary … the primary focus, but one can’t lose sight of what are the side effects and what is this patient’s long term quality of life going to be?

Brett: That is awesome. Thank you so much for your time today. We really appreciate it.

Suzanne: Thank you so much.

Lori: My pleasure.

'THINGS THAT MAKE YOU GO HUH?' END MUSIC PLAYS

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