Transcription:
Advances in Precision Medicine and Genomic Sequencing for Pediatric Brain Tumors

Melanie Cole (Host): Welcome to Back To Health, your source for the latest in heath, wellness and medical care; Keeping you informed so you can make informed healthcare choices for yourself and your whole family. Back to Health features conversations about trending health topics, and medical breakthroughs from our team of world-renowned physicians at Weill Cornell Medicine. I am Melanie Cole and today we are discussing precision medicine in genomic sequencing in pediatric brain tumors, and my guest is Dr. Jeffrey Greenfield. He's a board certified neurosurgeon who specializes in pediatric neurosurgery and he's the co-director of the Children's Brain Tumor Project at Weill Cornell Medicine. Dr. Greenfield, recent breakthroughs in next generation sequencing technology have made the capacity to investigate molecular landscapes of human cancers including childhood brain tumors. Let's start with a little definition. What is precision medicine? Does it go by another name?

Dr. Jeffrey Greenfield, MD (Guest): Well, precision medicine has taken on a number of broad definitions that are being used fairly ubiquitously throughout newspapers, and news commentators, and I think it's worth spending a minute just to define what it really refers to. Precision medicine really is a medical model that is a way to customize healthcare, and the way we define precision medicine within pediatric neurosurgery may be slightly different than the way precision medicine is defined in other parts of medical care landscape.

For example, personalized medicine and precision medicine sometimes are used interchangeably, and they're not exactly the same. The term precision medicine can really extend beyond treatment selections in terms of designing the types of treatment that might be available for a specific type of disease, whereas precision medicine has an overview for understanding how patient-specific genomic information can be used.

It's really something that has expanded and taken on a number of different meanings and definitions within the realm of oncology that we can certainly talk about throughout this interview.

Melanie: Tell us a little bit about the evolution of precision medicine. Has it advanced to the point where it can now impact the care of many children with brain tumors?

Dr. Greenfield: The evolution of precision medicine is really staggering to think about. If you just roll the clock back about fifteen years to the turn of the century when the first human genome was sequenced, this was an enormous undertaking at the National Institutes of Health and different pharmaceutical companies were all sponsoring and racing to get done, and it took several years and literally hundreds of millions of dollars to get to the point where the first human genome was sequenced.

That type of scope was really unprecedented at that time. If you fast-forward it now to 2018, we're looking at the ability to sequence the whole genome in a couple of days for several thousand dollars depending on where you're getting it done. So the ability to get the information in a timely fashion and act upon it has really dramatically changed, and that obviously impacts the ability to use that information because taking something from a six-month to a one-year timeframe, which it was just fifteen years ago, to the point where you can get a quick turnaround on information is really a dramatic change, and does significantly impact what we can do with the information.

Melanie: That is staggering, Dr. Greenfield, to hear how that's evolved. So then tell us about pediatric brain tumors. Have the treatments seen a change in the last twenty to thirty years, or are physicians still using treatments that are older? What had been the thought previously regarding pediatric brain tumor therapies?

Dr. Greenfield: Well when you narrow the lens down on precision medicine into pediatric brain tumors, the first question really is what's the need and what's the role for new therapies? Because I think there are some medical options that are available for other cancers that are wonderful, and within pediatric brain tumors, unfortunately that's not really the case.

And we're definitely better than we were twenty or thirty years ago when you look at the overall landscape of how we treat pediatric brain tumors, but I think we have to refine that down a little bit even more because when you're talking about adult brain tumors as sort of a distinction, there are only a couple of different types of tumors that we generally refer to.

In the pediatric landscape, however, there are literally twenty or thirty different types of brain tumors that we treat, and the vast majority of those have not seen a significant change in our ability to treat them effectively. There are some examples of dramatic success stories - so I don't want to paint an absolutely dire picture - but there are still some pediatric brain tumors that exist where there is literally a 0% survival rate.

So that is something that most people who are not involved in pediatric brain tumors don't quite understand when they hear a number like that. And this all comes together because when you think about a diversity of tumors, like I've explained to you of twenty or thirty different types, there's sub-types of pediatric brain tumors, and some with really staggeringly low survival rates, it does open up a lot of questions about why have we been unsuccessful at designing therapies, and then obviously segues into our conversation today about, "Well what potential role might precision medicine play in moving the needle a little bit towards success in these areas where we've been so unsuccessful in the past?"

Melanie: And this is such a sensitive topic, Dr. Greenfield, because parents- this is something that every parent dreads, and as you say, there's not been typically this great prognosis for children with any of those different types- many of those different types of pediatric brain tumors that you've spoken about. So what is the potential for this therapy to achieve successful treatment of brain tumors in children? Give us a little lesson on genomics, and what that even means.

Dr. Greenfield: Right, so the idea behind all of this, which has been utilized in lots of different fields, particularly oncology, is that if we understood a little bit more precisely what was going on within the tumor itself, understanding those switches or changes within the biology of those tumor cells, then perhaps we'd be a little bit more successful at picking out of a whole long list of possible medications, those things which might specifically work in that tumor.

So the example here is that if you look at a basic type of brain tumor that we see in children called medulloblastoma, which is the most common type of brain tumor in children, they all look fairly similar on an MRI scan. And even if you look under a microscope, they still look really similar, but if you look at the genomics - which means looking at the actual signature of the DNA within those tumors - what comes out of that analysis is a real broad distinction between several different classes of that single appearing tumor into classes that are defined by their molecular signature, and that molecular signature now defines what type of medication they may be treated by more successfully, and even more powerfully, which children may not need the most toxic types of treatment.

And so it is a real spectrum of information that you can get from this type of analysis as we're designing therapies and we're also whittling back therapies that may not be necessary, and can be extremely toxic in children.

Melanie: As this emerging technology advances, Dr. Greenfield, do you think this is set to be a game changer in the diagnosis and treatment of the disease? Where do you see it headed in the near future?

Dr. Greenfield: I think there are a number of hurdles that we need to overcome until this becomes mainstream within our field. I think we've crossed over from this type of analysis being purely a scientific endeavor into one in which we are now making substantial therapeutic decisions and medication decisions. We're able to give better prognoses to families and give more information to the treating oncologist.

But for this to really enter into the mainstream of our treatment and become, as you refer a 'game changer,' I think there are still a number of things that need to occur. The first of those is that we need to really think about this as part of our standard of care from the very beginning of cancer diagnoses in children with brain tumors. What I mean by that is we often find ourselves asking some of these tough questions very late in their treatment course after they've already received, what we refer to commonly as, 'standard of care.' And unfortunately, standard of care, which is often unsuccessful, also has side effects with respect to how it changes the biology of the tumor.

And so what I mean by that is if we were able to identify every patient from the very beginning and get DNA from their tumors and do these analyses from what we call a 'genova' or naive tumor, we would get radically different information on how to treat that tumor than when we get that same information from a tumor that, for example, has been treated with radiation or chemotherapy often multiple times.

And so while we're making some really nice impacts and are starting to make headway, it still has not reached sort of the mainstream consciousness that this is something that should really be thought about up front, and one of the reasons for that is that it's not offered everywhere, and so parents are naive to the entire landscape of pediatric brain tumors. They're often in shock when they get the diagnosis, they know nothing about it, and they're taking information from whoever is giving them that information, whether it's the emergency room, or the treating neurosurgeon that sees them first. And so hopefully this type of program and others like it can start educating the general public and healthcare providers to know that it really does make a difference where that treatment is given up front, because sometimes you can't go backwards in time to get the information that you would have liked to have had at the beginning.

Melanie: What a great segue, Dr. Greenfield. So what can parents expect for their children as far as you're speaking about getting this information up front, and some of the consequences in the way it had been treated; radiation and such. Tell us what are some of those consequences that children have been subjected to as standard of care, and what do you see would be different now? Tell the parents how you see this changing the treatment therapies for their children, and the results- not necessarily the results, but some of the side effects from some of those treatments.

Dr. Greenfield: Sure, well I'll give you a couple of examples that maybe can illuminate this for the listeners. The first is just to imagine that you haven't had sequencing done of the tumor up front, and you don't have all that genetic information. Whether or not you make any treatment decisions based upon that up front, let's just say for example that you've had a biopsy or surgery and the tumor has been removed and you're onto second treatment which is often chemotherapy or radiation. If that tumor recurs, and at that point you choose to utilize precision medicine as an option to consider other treatment modalities, then what you've lost is the reference point against which that tumor might be better defined, meaning that when you look at a broad array of mutations in a tumor, it's not always clear what's there from the beginning and what is there as a secondary effect.

And so having the comparison is often very powerful to know what has happened to the tumor to cause it to recur, change - which is called transformation - or spread, which is often referred to as metastasis or dissemination. So having these different time points is incredibly powerful, and some of our most remarkable cases where we've utilized precision medicine, we can have up to six or seven different time points across the entire time of a disease from diagnosis all the way through multiple treatments and recurrences, and what evolves from that picture is a very detailed and kind of a- in a way, a beautiful evolutionary tree of all the mutations that have been there since the beginning and those that have been joined on with the initial mutation, so to speak, to allow the tumor to either escape the therapy that it was currently on or to transform in some way.

So what that means is that at recurrence, you might have a different tumor, and you might have a different treatment option available, but without that prior knowledge, that may not be available.

The second example I wanted to give you was that of medulloblastoma, which are for a tube of four. And what's really powerful in pediatric neuro-oncology, when you talk to parents who have been through this and have come out on the other side, is that they're as equally concerned about treating the tumor as they are about limiting the side effects and the toxicity of the treatments. And so twenty or thirty years ago, kids were being cured from this type of a tumor, and being left with really devastating side effects on their cognitive development, on their hormonal development, on their vision, on their growth, and so there was a significant cost associated with cure. And now we know that there are certain tumors that don't need some of these toxic treatments, and you can't define those without getting the molecular landscape performed through genetic analyses.

And so it really is absolutely crucial now to- at least the treatment of this specific tumor, for us to be able to advocate to the parents, "Look, this tumor is not as bad as the other varieties. You don't need to do this high dose radiation in your young child because the side effects are so toxic, and what might have been scary to consider ten years ago forgoing something like the highest dose radiation, we're much more comfortable doing today because we know the prognosis is so much better based upon the sub-class analyses.

Melanie: That's a very good description, Dr. Greenfield, and you made it so clear and understandable. So, as targeted therapies are likely to be most effective when they're matched to those specific abnormalities within those tumor cells, in everything that you've described for us today, take us from lab to clinic with precision medicine for pediatric brain tumors; how this can now be a reality and what parents can expect in terms of timeline and advancements and side effects.

Dr. Greenfield: Yeah the timeline question is an excellent one, and it's something that I spend a lot of time thinking about because we are dealing with children who don't have a lot of time, and in whom decisions need to be made on a fairly rapid basis. So I will walk you through the process from the diagnosis until the first possible opportunity that precision medicine may be offered, and give you a glimpse of what's happening in the laboratory at the same time that progress is being made on the oncology side when the child is actually being treated.

So, envision a child who's diagnosed, they end up in an emergency room because of a neurologic symptom, and they are diagnosed with a brain tumor and end up in the operating room. If you end up in our operating room at Weill Cornell Medicine, what happens is that a precision medicine algorithm is automatically initiated, and what that means is that there is a piece of the tumor, and often multiple pieces from different parts of the tumor, along with sometimes fluid from the brain called CSF, and the patient's own blood.

All those samples are rapidly collected and taken both to the pathology laboratory but also to the Children's Brain Tumor Project where we not only isolate DNA and RNA to do these analyses to find out what we referred to before as the signature or the personalized landscape of that child's tumor, but we also start growing those cells in dishes in the laboratory, and at the same time we're actually implanting those cells into specially designed mice that allow us to grow the tumors within a brain environment.

And so a lot of people know about the precision medicine part that exists within the traditional laboratory where the DNA is isolated and you get back a report on paper. The more exciting part for us is that we can now grow children's cells both in dishes and in animals and then test those cells against a wide array of different drugs based upon what that DNA analysis suggests to us. This is called high throughput drug screening and is really state of the art right now, allowing us to essentially test hundreds of different drugs against the patient's actual tumor.

And what this does, is it refines even further for us some of those decisions that might be available for children when you're comparing - again, what has been referred to as the standard of care against something which may be a little bit more personalized, a lot more unique for that child. This is something that we call N-of-1 medicine. N-of-1 medicine essentially refers to the idea that every child is their own personalized study, meaning that this is not a clinical trial that pits one drug against another looking at hundreds of children over many years. This is essentially taking one child's tumor, pitting it against hundreds of different drugs, and figuring out the exact cocktail and recipe of drugs that best treats that child's tumor in a dish, in an animal, and hopefully that translates to in the child.

Melanie: That's absolutely fascinating, Dr. Greenfield. Absolutely amazing what you are doing. And as a wrap-up and summary, what else would you like listeners to know about precision medicine and its uses in pediatric brain tumors? Give hope to the parents of children with brain tumors for this exciting research that you're doing and the possibilities for better treatments.

Dr. Greenfield: I think the exciting part about precision medicine is that there really is now an amazing collaboration that we're beginning to witness between what used to be seen as disparate parts of the community. Parents have been such a big part of drawing attention to the lack of funding and the need for new therapies in pediatric brain tumors that it's finally gotten the attention of the federal government, and there has been a large precision medicine initiative, as you likely know, put forward by Barack Obama and it was Joe Biden's big idea to start creating pipelines of resources for researchers to actually study precision medicine.

So the government has finally gotten behind this and understood the need. The pharmaceutical companies are also a huge part of this. Traditionally, there has not been a big push for new drugs in pediatric brain tumors because the market is relatively small. It sounds like a really crass, terrible thing to say, but there's literally no incentive for pharmaceutical companies to investigate drugs for a type of tumor that might affect 200 or 500 children a year, when they're busy trying to design drugs against things like lung cancer and prostate cancer which affect hundreds of thousands.

And so it has taken some time to figure out that there is a moral obligation to find a better way and a better treatment, and all of this now has come together at the same time that precision medicine is making it clear that as long as we have access to money to do the research, and have access to all these drugs that we might figure out as being the one that any individual tumor might respond to, I think there's tremendous hope that this is going to become mainstream and part of every child's treatment algorithm going forward. It's not going to be something specialized that you only need to go to one or two places to go to receive, but rather will become the standard of care for any child who's diagnosed with a pediatric brain tumor; those words that no parent really wants to hear.

Melanie: And certainly they don't. This is captivating, what a great segment. Dr. Greenfield, thank you so much for coming on, for sharing your expertise, and explaining so very well this very complicated topic, but putting it into a way that parents can understand, because this is such a devastating diagnosis for parents, and you've explained all of this exciting research so well. Thank you so much again. This concludes today’s episode of Back To Heath. We’d like to thank our listeners and invite our audience to download, subscribe, rate and review Back To Health on Apple Podcast, Spotify, and Google Play Music. For more health tips go to weillcornell.org and search podcasts. Parents – don’t forget to check out Kids Health Cast!