The Bioinformatics CRO Podcast

Transcript of Episode 46: Amar Gajjar

Disclaimer: Transcripts may contain errors.

Angel Belgard: [00:00:00] Welcome to The Bioinformatics CRO Podcast. I’m Angel Belgard, Chief Medical Officer at the Bioinformatics CRO and today I’m joined by Amar Gajjar, chair of the Department of Pediatric Medicine and the Scott and Tracy Hamilton Endowed Chair in Brain Tumor Research at St. Jude Children’s Research Hospital. Welcome Amar.

Amar Gajjar: [00:00:20] Thank you Angel. Good to be here.

Angel Belgard: [00:00:23] It’s good to have you. So working in St. Jude in pediatric brain tumors, it seems that much of your research focuses on pediatric medulloblastoma, which is among the most common malignant pediatric brain tumors. Can you tell us a little bit about this cancer?

Amar Gajjar: [00:00:41] Yeah. So when I started, I joined the faculty that was charged given to me is develop a medulloblastoma program. And that’s what I focused my academic career on for the last almost 25 years. So this is a tumor which occurs in the entire spectrum from infants to the pediatric age group to adolescent, young adults, and also very rarely in older adults. We used to treat this disease as if it was a single disease entity. But what we’ve learned painstakingly through all the work that St. Jude investigators and investigators in other big centers like Toronto and Boston, in the U.K. and in Germany have demonstrated that actually medulloblastoma is not a single disease, but a compendium of four very distinct molecular diseases, which have very distinct cells of origin, distinct molecular changes and very distinct outcome based on a treatment. So we’ve really built on that theme and really refined and continue to refine our risk model because it has allowed us to reduce therapy for patients which have good outcomes, which do not require high doses of radiation therapy, so that we can not only just cure them, but leave them neuro cognitively intact so that they can complete their education, go to college, live independent social and financial lives. So it’s a dual mission, curing children, but also curing them in a way that they can be functional adults.

Angel Belgard: [00:02:25] Certainly both of those are important with the molecular subsets that you see. How closely do those line up with the clinical presentations?

Amar Gajjar: [00:02:35] The clinical presentation and the molecular subset based on the imaging, one subgroup, the sonic hedgehog subgroup, the tumors are hemispheric in the cerebellum. The Wnt subgroup, there’s an 85% are in the fourth ventricle. There’s 15% of them are in the angle or CP angle as we call it. And then we have group three, group four, which don’t have any predilection for site. But we can always say when a child shows up in the ER and has a large hemispheric tumor, it will be hedgehog. If it’s midline tumor or a CP angle tumor in an older female, it’s going to be a Wnt tumor. So you get a little bit of inclination on the clinical presentation. In the infants, majority of them are going to be sonic hedgehog. About 65% of them are going to be sonic hedgehog. About the remaining 25 to 30% will be group three. So you start at least getting an idea of what you’re going to be dealing with before you get the tissue in hand.

Angel Belgard: [00:03:42] And prognostically my guess would be that there some delineation with that, too.

Amar Gajjar: [00:03:47] Yes. So the Wnt tumors generally do very well. The sonic hedgehogs based on their molecular features, there’s a group which does very well and a group which has inferior outcome. So it’s not as simple as just the label. It’s again, you dig deeper into the molecular characteristic of each subgroup and then you have to look clinically whether the tumor has spread, whether it’s metastatic disease, whether they could get all the tumor out at the time of surgery. So then you start drilling down deeper and deeper until you come up with a comprehensive risk stratification.

Angel Belgard: [00:04:20] Tell us a little bit about the risk stratification and how you were able to come up with the adaptive radiation therapy for the different groups.

Amar Gajjar: [00:04:29] Currently we are using the lowest dose of radiation therapy for the Wnt tumors because they do best. We’re using an intermediate dose for the ones which are molecularly and clinically good risk. And then we use the higher dose radiation therapy only for the patients which have got high risk disease or metastatic disease. And that study is the first in North America actually in the world. And we are watching the numbers very carefully. The study is being monitored by an external data safety monitoring board, just so that the reductions in therapy that we’ve made, not just radiation and chemotherapy, are not going to adversely impact the outcome for these children. So we’ve got about 650 patients enrolled on that study, and we’ll accrue for a year or more before we’ll open our next study and fine tune the risk even more.

Angel Belgard: [00:05:20] At this point in the study, are you already seeing based on neurocognitive function following the therapy? Are you already seeing differentiation in that?

Amar Gajjar: [00:05:30] Yes, but there’s a big change. We now treat these patients with proton beam radiation compared to photon, which was the older way of treating children. So I think the proton beam children are getting less radiation to the normal brain. And I think that’s been a big game changer as far as their neurocognitive outcome.

Angel Belgard: [00:05:51] That’s fantastic. You have studied, like you were saying ongoing neuropsychological outcomes for them because this is a cancer that can affect children of all ages. How do you assess for those children that are too young to complete neuropsychological testing?

Amar Gajjar: [00:06:09] Not all of them get the same test. So depending on the age of the child, there are different tools which have been sort of verified as they’ve been developed. So for the younger children, they use completely different tests. For the older children, adolescents, they use completely different tests. And there are some children who just cannot finish the cognitive evaluations because of the time required and they just can’t focus. So we try and sometimes we split the time up to shorter two day tests. But sometimes parents can’t invest the time. They’ve all got to get on to jobs. So we try to do the best we can for the time we have with the children when they visit the campus.

Angel Belgard: [00:06:48] It looks like literacy is a marker that you’ve used quite a bit to incorporate all the different neurocognitive skills. Can you speak a little bit about that?

Amar Gajjar: [00:06:56] Instead of Global IQ, we have now split the domains up into processing speed, which we think is the most important sort of feature of cognitive outcome. And that really is the speed at which a child receives information, processes the information, stores the information, and then has the output. And we find that these children who have had radiation therapy at a younger age, their processing speed is slowed down, which then reflects their work output in school and generally with a little bit of adjustment, a little longer time for their tests and a longer time to complete their homework. The parents invest in their children. They do okay, but it’s easier said than done. So because the school systems have to be accommodating, the teachers also have to understand because the children look good, but they’re just not performing where they should be. And some teachers in the bigger school systems have seen children with brain tumors who have had therapy before. And they understand, but somewhat in the rural systems, the smaller classrooms are not that much experience. Sometimes the teachers do not completely understand what is going on.

Angel Belgard: [00:08:11] I know that there will be great differentiation with this, but do you ever see a neurological catch up like a number of years out at which point you’re not seeing significant deficits anymore?

Amar Gajjar: [00:08:25] No, unfortunately that doesn’t happen. We are working to remediate some of the deficits, and that’s a big area of research which investigators at St. Jude and other places are now leading because we’ve done a lot of work documenting the deficits. But now we’re saying what can we do about it? So I think this is a huge area of research. We are working with the children with exercise intervention, reading intervention, cognitive intervention, and these are areas which are being actively researched.

Angel Belgard: [00:08:54] And also looking into hearing deficits.

Amar Gajjar: [00:08:58] You’re absolutely right. So hearing loss is a big morbidity in these children. So we’ve been very careful. We’ve done studies. We’ve reduced the dose of cisplatin. Again with proton beam, we are seeing a lower incidence because it is preventing radiation to the middle ear and the cochlea, all little, little things which seem trivial, but then they impact the long term outcome of the child. So if you’re cognitively slow and then you have hearing loss, it’s much harder for that child to sit and pay attention and get what the teacher is saying. So at least if you can prevent the hearing loss, that’s a huge victory.

Angel Belgard: [00:09:38] Absolutely. Now, in addition to these neurocognitive outcomes for children who are diagnosed with medulloblastoma, your research also focuses on those children who are unfortunate to have relapsed medulloblastoma?

Amar Gajjar: [00:09:50] Yeah, unfortunately we are curing about 75 to 80% of all comers, with still 20, 25% whose tumors come back. And we are trying to devise newer, smarter therapies and we test them out in the children who have recurrent disease to see whether there’s any efficacy. So this is a constant effort which is going on within our group and other large groups in North America, hoping to then move some of these therapeutic options in the newly diagnosed or the upfront setting.

Angel Belgard: [00:10:19] What molecular subtype observations have you seen between the primary tumors and the relapsed cases?

Amar Gajjar: [00:10:27] Very good question. We just published that this year. So a couple of things. Suppose it’s a sonic hedgehog at the first time, it’s going to remain sonic hedgehog the second time around. It’s, I mean it relapses. It doesn’t switch its lineage. What it does do is pick up additional mutations depending on what test you do sequencing or if you do an expression array. The other thing we’ve learned is that we used to just presume that these tumors were recurrent medullos. There’s a percentage of these tumors which are not medulloblastoma, which are gliomas. You can call them subsequent, secondary radiation induced. And there are some children who are genetically predisposed to develop brain tumors. So I think 10 to 15% of these turn out to be glioma. So I think the field has now learned to biopsy these and make sure that you’re dealing with a medullo rather than just presuming that it’s a medullo.

Angel Belgard: [00:11:21] What would you hope to see in furthering your study and where would you branch out next to?

Amar Gajjar: [00:11:27] Well, we want to cure 100% of these children diagnosed with this tumor. So won’t happen in my lifetime. But I wish my team will continue working and mimic the success in ALL that we’ve seen. When St. Jude opened, 4% of the children were getting cured, and now we’re up to almost 97%. We’ve got a room. But when I joined St. Jude, we were curing about 72% of ALL. And now in my lifetime I’ve seen a 25% jump. We’re already at about 75% so we’ve got a little ways to go.

Angel Belgard: [00:12:02] That’s pretty incredible. What do you think are some of the most outstanding questions related to pediatric medulloblastoma?

Amar Gajjar: [00:12:09] Well, I mean there are lots of questions as to the molecular makeup. Why is this disease so aggressive? Some of the younger age groups where we don’t use radiation therapy, so we really stuck with surgery and chemotherapy. What is the vascular pattern? Why does some tumors tend to metastasize and grow, whereas some tumors like Wnt tumors very rarely metastasized? So there’s a lot of biological questions which we are looking at as we are dissecting these tumors. We know the reason why Wnt tumors now have such a good outcome because they secrete a chemical which breaks down the blood brain barrier. So they see a much higher concentration of chemotherapy. So that’s why it’s very effective. Some of these secrets we are getting to know and then some of these secrets left to be explored.

Angel Belgard: [00:12:57] Among the treatments that are up and coming, it sounds like you’re pretty excited about proton beam.

Amar Gajjar: [00:13:03] The proton beam is a form of radiation therapy. As I said, we hope most of the children in North America will be treated with proton beam. I think their centers are getting more available to the public. They’re clustered in a few areas, but they are expanding. So it’s a huge advantage, proton beam therapy. Also surgical resection, the tools available to the neurosurgeons when I started versus the tools available when they’re operating today, they have a lot more advantage technically. When I started, there was no MRI. Everybody was using CT scan, and now we’re looking at 3 Tesla MRs, which the anatomical description, the anatomical detail is just absolutely amazing. You can’t pinpoint to one thing, but every technological advance, if you can harvest it will impact your treatment outcome.

Angel Belgard: [00:13:56] I’m wondering a little bit about your path into science and into pediatric oncology. At what point did you know that you wanted to become a doctor or a pediatrician or an oncologist?

Amar Gajjar: [00:14:08] I come from a family of doctors, so I’m third generation and my daughter is a fourth generation. So next year our family will finish 100 years in medicine. So the fact that I was going to be a doctor, I decided was when I learned to talk probably. I came to the United States and I met a mentor of mine who told me, Amar you need to do pediatrics because you can focus on one disease and you can cure it. Otherwise, you have adult patients that have got obesity and hypertension and lung and this and diabetes and all these chronic morbidities. And then you have to treat everything. Now, of course when you are 22 years old, such a profound statement like that, you don’t understand it. But I knew this man was an incredible mentor and a very, very smart man. So I said, listen you know what? Listen to what he says. So that’s how I went into pediatrics. And then again focus back, I wanted to do oncology. So as a second year resident, I came to St. Jude, did an elective, and then I said, Listen, this is my home. I came back, did my fellowship, heme onc fellowship, and they did a year of neuro-oncology fellowship and joined the faculty. And it did turn out that I treat all neuro oncology, but I focus on one disease.

Angel Belgard: [00:15:25] Your advice from your mentor really rang true?

Amar Gajjar: [00:15:27] Absolutely.

Angel Belgard: [00:15:29] Now, you did your medical training at Grant Medical College in Mumbai, is that right?

Amar Gajjar: [00:15:34] Yes. Yes.

Angel Belgard: [00:15:36] How different was your experience coming from there and then joining the residency at University of South Florida.

Amar Gajjar: [00:15:43] In India, the numbers are amazing. I mean the population is huge and we look after a lot of patients and we don’t have the kind of infrastructure that is available in the United States. And I can speak not just India, but a lot of the Asian countries because I travel. I used to before COVID. In the US, we are lucky that we have all this technology to help us and have better results because of that.

Angel Belgard: [00:16:10] So certainly working with cancer patients in general can be emotionally taxing as you’re talking to families and breaking pretty difficult news on a daily basis and then more so working with young children. How do you cope with that ongoing?

Amar Gajjar: [00:16:28] Well, it’s difficult. But remember, I’ve been very, very fortunate to have been surrounded by a phenomenal team of people. We have focused and motivated and dedicated to our roles in our team. And I think that makes the burden much lighter, that it’s not just one person who makes a difference. It’s everybody who’s sort of rooting for the success of the team. And I think if I were isolated and working alone in a team which didn’t understand or kind of didn’t share the vision or the mission would never be the same. So I mean, if I had to look back at my career and think about what’s the most important thing, and I would say my team, nurses, nurse practitioners, my regulatory team, my data managers, research nurses, [Kristen], my PR, she holds me accountable.

Angel Belgard: [00:17:20] Among your family members since you come from a pretty extensive medical background in the family, did they do their training also either in the US or in the UK?

Amar Gajjar: [00:17:31] Yeah, all of them. My grandfather started it and he was in the UK. Next year it’ll be 100 years ago that he started his medical school in London.

Angel Belgard: [00:17:40] Wow. Are any others in oncology?

Amar Gajjar: [00:17:45] No. No. They’re all pathologists.

Angel Belgard: [00:17:47] Oh really? All of them?

Amar Gajjar: [00:17:48] I’m that way the black sheep. My original idea was to be a hemato oncologist, to have a leukemia practice and have a lab. But that didn’t pan out though I did practice ALL for almost ten years.

Angel Belgard: [00:18:00] What sorts of advice would you have for people entering the field of medicine today, perhaps advice that you bestowed on your daughter?

Amar Gajjar: [00:18:08] Don’t do it for the money. Make sure that you love what you do. Because if you’re doing it for the money, there are many, many smarter ways to become rich. Medicine is not one of them.

Angel Belgard: [00:18:18] That’s true. It seems like a better way to get into debt, right?

Amar Gajjar: [00:18:22] Yeah.

Angel Belgard: [00:18:23] And for those wanting to move from purely clinical medicine to clinical research, do you have advice for them?

Amar Gajjar: [00:18:30] Well, I think having the right environment, having the right supportive mentors and really putting the time and sweat equity into it is something which you got to think about. It’s not all fun and games and then your family needs to understand what you’re committing to and support it. Many times I feel that people who are lucky enough to have supportive families have a much better chance because it’s long hours. None of this is, I mean if the idea is at 5:00 on Friday, I’m going to switch off and come back on Monday at 8:00. And in between, I mean there’s a certain amount of time, dedication, thinking, reading which one has to put in. And I think having family support for that is very important.

Angel Belgard: [00:19:15] Over the years, you’ve talked a little bit about the changes in neurosurgical approaches and the differences in imaging. What other kinds of changes have you seen in the field of medicine throughout your training?

Amar Gajjar: [00:19:27] As I said, the supportive care has improved tremendously. I mean, I remember the days when we didn’t have the simple thing like antiemetics, nausea, medicines and now the children have got so much better control. Pain medicines, we have appropriately used and dispensed long term pain control. Again if you start quantifying, there’s no one single thing, but there are multiple advances which you package together makes a big difference. Remember when I started, we didn’t have even growth factor support. So G-CSF was something which was new. We really started using it in 1998. It was a new thing and now we give it the duration of time. These children have their counts dropped by 4 to 5 days, which is huge.

Angel Belgard: [00:20:19] Is there anything within the system that kind of shouts out as the next thing that clearly needs to be changed?

Amar Gajjar: [00:20:27] Well, one of the things we’re getting better at because we’re getting so much genomic information on these tumors. We’re looking at germline predisposition syndromes, patients which are going to have because of their genetic makeup toxicity to certain drugs adjustments because of the genotype phenotype correlation. So there’s a lot of that advancement and insight that we have just started understanding and approaching. The first human genome took two years to sequence and now we get the result in two weeks commercially. That time President Clinton and NCI and there was a private person attempting to do the same and Clinton had to go and make peace that they will sequence, put the results of those things back to back so that one person wouldn’t be a clear winner. And now we just order it as a lab test and within two weeks we have the entire human genome sequence. So you can imagine the pace at which, science and medicine has moved along and the information highway that we are on.

Angel Belgard: [00:21:30] And certainly the outpacing potentially of where the forefront of that is and where medical education is along the way.

Amar Gajjar: [00:21:37] Oh, yeah, absolutely. The current generation of medical students, I tell them the residents. I said this will be regular sort of clinic talk for you guys at a very basic level. So if we know that you’re going to have a bad reaction to this medicine, this will be a report that will alert you right away. Right now, we are defining all these things, but a point will come when your system will not allow you to even prescribe this stuff.

Angel Belgard: [00:22:04] Yeah, the concept of precision medicine has really come a long way in just the last ten years even.

Amar Gajjar: [00:22:10] Long ways. Yeah, absolutely.

Angel Belgard: [00:22:12] What are some common misconceptions about medicine or cancer that you see with your patients or with your trainees?

Amar Gajjar: [00:22:21] Misconceptions in pediatric oncology, patients are young and families do a lot of hunting on the Internet. And I in fact encouraged them. I said, do whatever searching you have to do, but then do come back if there’s something that you’re reading. Just because it’s on the Internet doesn’t mean it’s true. It’s not verified. Anybody can put anything on the Internet. And I think sometimes it’s a relief to these families because it opens up an open dialogue. Now, adult oncology may be very different and they may run off. But even then, we have people who go on vitamin D or orange juice. There’s all kinds of opinions on chat groups so it really depends on what these people are reading and who is influencing their thinking. But I find that having an open discourse, opening up that communication channel, you can hold them closer and have an open discussion with them. Give you a common, very common mistake. So they’ve understood that when you do a PET scan, the tumor is taking off FDG glucose. They say the tumor is eating glucose. So then they think if the tumor is growing on glucose, why don’t we eliminate glucose from the diet of the child? And then they go on this kick and they completely starve this poor patient. And I tell them our body is made to make glucose. Our brain works on glucose. You may think you’re not feeding glucose, but the body will make glucose. And so try to common sense way sort of guide them so they don’t go crazy or that ketotic diet. Some of them go on that. These are the kinds of things. They go off on a tangent. But generally if you talk to them and make them understand, most people will listen. There’ll be some people who, you know, then they come in with severe ketones in the urine. They’re losing weight because they’re feeding them this stuff.

Angel Belgard: [00:24:18] Yeah and that’s something you definitely want to convey that not all of these things are harmless, even though they’re nutritional adjustments.

Amar Gajjar: [00:24:27] Yeah. Yeah. I mean absolutely. I mean, we’ve had kids who have super high levels of vitamin D and then they’re getting renal stones. And I mean, there’s all kinds of stuff. Sometimes they’re LFTs are completely out sky high. And I said, What’s going on? And then they’re feeding them some herbal tea. And I mean, they’re doing all kinds of crazy stuff. But fortunately it’s the minority. And generally we catch it. Usually they settle down.

Angel Belgard: [00:24:51] Well, wonderful. Aside from medulloblastoma research, your research also focuses on rarer brain tumors as well. Would you talk a little bit about those?

Amar Gajjar: [00:25:02] Yeah. So again, historically we used morphology and how the tumor looked under the microscope. And commonly all these tumors are called small, round [] cell tumors because they all look very similar. Now we’ve got molecular diagnostics and molecular tools. So even if they look similar under the microscope, they’re molecularly very distinct. So we’ve got new entities like ATRT Atypical Teratoid Rhabdoid Tumor, ETMR and other what we used to call supratentorial PNETs, into very molecularly distinct. So they look the same under the microscope. But when you start doing the genetics and some of the immunohistochemistry tests, that separates out each distinct entity. And that is again helped because ATRTs in younger children, they have germline predispositions and they’re very aggressive. They are in turn made up of three molecular subtypes and we are trying to find specific drugs for each of the subtypes which normally 30 years ago would be all considered medullo. So all that fine tuning is coming at a very rapid pace.

Angel Belgard: [00:26:10] How widely available is that fine tuned diagnostic sequence? Is it only available to large institutions?

Amar Gajjar: [00:26:18] Yeah, but most pathologists who don’t see the volume will send it out for consults. So they know. I mean big centers which see large volume, it makes sense for them to invest because they’ve got enough positive and negative control. They can test their strains. They can test their FISH probes. If you’re a center which sees ten of these patients a year, it doesn’t make sense. Less than one a month. It doesn’t make sense because every time you’re going to be shaky, whether this stain is correct, whether it’s working or not. So you’re almost cost effective to just send it out.

Angel Belgard: [00:26:51] Well, thank you so much for speaking with us.

Amar Gajjar: [00:26:54] Thanks for the opportunity. Good talking to you.

Angel Belgard: [00:26:57] And talking to you as well.