Hodgkin Lymphoma is the most common cancer type in adolescents and young adults. But until recently, very little was known about the biology of the disease. Enter, Dr. Lisa Roth, Director of Pediatric Oncology at NewYork Presbyterian and Weill Cornell Medicine, and her team of researchers. Their tireless work to pin down the difficult biology of Hodgkin Lymphoma has led them to became the first scientists to map the entire Hodgkin Lymphoma genome, uncovering new pathways to treat this historically understudied cancer-type.
In 2012, Dr. Lisa Roth had just landed her dream job as a research scientist and attending physician at NewYork-Presbyterian and Weill Cornell Medicine. But her world came to a screeching halt when she discovered a swollen lymph node on her neck, and was soon diagnosed with the exact type of cancer that she had dedicated her career to studying and treating: Hodgkin Lymphoma. After that experience, Dr. Roth was more determined than ever to uncover the biology of this notoriously difficult to study cancer. Dr. Roth, now Director of Pediatric Oncology and Associate Professor in the Departments of Pediatrics, Medicine and Pathology and Laboratory Medicine at NewYork-Presbyterian and Weill Cornell Medicine, tells the story of how she and her team became the first researchers to sequence the entire Hodgkin Lymphoma genome, opening doors for precision and preventative treatment options.
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Dr. Lisa Roth: I think there have been a few times in my life where I've been like, this, this is it. This is exactly where I want to be.
Catherine Price: Dr. Lisa Roth clearly remembers the moment when she realized she wanted to be a pediatric oncologist.
Dr. Lisa Roth: When I was choosing a specialty, I remember sitting down with a pediatric oncologist who was walking a family with a five year old with leukemia through that new diagnosis and that horrible moment where you realize that your child has leukemia. And she did it with such compassion and offered this family so much hope for their child. I felt like this is something that, you know, if I could serve in that role, that I'd really be making a difference in the lives of these families.
Catherine Price: During her fellowship in pediatric hematology and oncology, Dr. Roth found that in addition to caring for young patients and their families, she also loved being in the lab.
Dr. Lisa Roth: The laboratory science was so interesting to me, kind of unexpectedly. I had barely touched a pipette before, [00:01:00] but I found the science of this field is so exciting.
Catherine Price: As she continued working in the lab, Dr. Roth found a research focus that she was passionate about: Hodgkin’s Lymphoma.
Dr. Lisa Roth: So Hodgkin lymphoma is actually the most common cancer type among adolescents and young adults. [But] there's a lot of challenges in understanding the disease. I found the science and the pace of it to be fascinating, and kind of moving between these two worlds of the lab where you're making discoveries for the next drugs, you know kind of the next big thing that will help to advance outcomes [and] the clinic where you're treating patients. I found that mix to be amazing.
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Catherine Price: After her fellowship ended, Dr. Roth landed her dream job as a physician scientist. She’d split her time between researching Hodgkin's Lymphoma in the lab, and working in the hospital treating pediatric patients as an attending physician at NewYork-Presbyterian and Weill Cornell Medicine.
Dr. Lisa Roth: So things were going great. My husband and I had just been married a year before, we had been [00:02:00] planning our lives together and, you know, starting a family and my career had just been taking off. Then, my whole world changed.
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I felt a lymph node on my collarbone and I got a CAT scan. I actually read my own CAT scan and learned that that lymph node on my collarbone was actually part of a much larger tumor in my chest. And I myself was diagnosed with Hodgkin’s Lymphoma. The exact type of cancer that I had devoted my career to studying.
And so as happens for all of our patients, my whole world came to a screeching halt.
I had to undergo chemotherapy treatment and have kind of now had the experience of being exactly where my patients are, in that infusion chair, receiving chemotherapy. And so having that perspective is a life altering experience. When the reality hits, it's just kind of a, like, almost an out of body experience that this is happening to you. But I was fortunate. I went into remission. And this year I’m celebrating 10 years [00:03:00] cancer-free.
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Dr. Lisa Roth: I think when your normal life is stripped away, it's not the big things that you're excited to come back to, but it's a lot of little things that you don't even think about.
So it was really exciting to get back to work and get back to life where it had been put on hold. Everything that I do is with such meaning and through such a different lens having been through this experience.
Catherine Price: After her own experience, Dr. Roth was more determined than ever to delve into the difficult biology of Hodgkin’s Lymphoma. She knew that if they could crack the genetics of the disease, it would open the door for targeted, novel therapies, and allow more patients to beat this cancer, just like she did.
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Dr. Lisa Roth: I think adolescents and young adults with cancer in general can slip through the cracks and that this is a group that historically has not been the focus of research. Advancements have not been as fast as they could be. The [00:04:00] research in the laboratory is important to understand the biology of the disease.
Catherine Price: I’m Catherine Price and this is Advances in Care.
Today, Dr. Lisa Roth tells the story of how she and her team became the first researchers to fully sequence the Hodgkin’s Lymphoma genome, revealing the biology of a cancer that’s notoriously difficult to study. Through the genetic information they uncovered, they are beginning to harness the biology of the disease, and create new pathways for novel therapies to treat adolescents and young adults battling cancer.
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Dr. Lisa Roth: Genetics is a field that has really taken off in the last 20 years. Studies that would take months, if not years, and cost hundreds of thousands of dollars can now be done overnight for a few hundred dollars. So the advances in the ability to perform genetic sequencing have really skyrocketed. [00:05:00]
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Catherine Price: This newfound accessibility has completely changed the pace of cancer research. It’s given researchers the ability to study different types of cancer and map that cancer’s unique biology.
Dr. Lisa Roth: Understanding how cancer occurs and what are the sequence of events that lead to the cancer itself, can help you understand which genetic alterations are the key genetic alterations, that you want to target with a new therapy, and can lead to the development of therapies, and for some cancer types, even preventions.
And so that has been really important for cancer as a whole. And you can sequence pretty much any cancer type using these new technologies. Except Hodgkin lymphoma.
Catherine Price: That’s because in order to perform genetic sequencing on a cancer, you, of course, need malignant genetic material to study. And the malignant cells in a Hodgkin’s Lymphoma tumor, called Reed Sternberg cells, are incredibly hard to find within the tumor itself. [00:06:00]
Dr. Lisa Roth: Trying to sequence the Hodgkin and Reed Sternberg cells is like finding a needle in a haystack. So they're less than 1 percent of the cells in the actual tumor. The rest of the cells are actually the patient's own normal immune system trying to battle this cancer. So those immune cells that surround the Reed Sternberg cell, all those normal cells, are actually essential to the survival of the Reed Sternberg cell.
And so if you were to send a Hodgkin lymphoma tumor for standard genetic sequencing, you wouldn't find those Reed Sternberg cells, and you would just be sequencing the normal immune cells that are in the tumor, and you would learn nothing about the patient’s cancer or about how to develop novel drugs.
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Catherine Price: When they first set out to sequence Hodgkin’s Lymphoma, the challenge Dr. Roth and [00:07:00] her team faced was clear: to find a way to isolate enough of the malignant Reed-Sternberg cells from the normal immune cells in the tumor, to be able to perform genetic sequencing. Specifically, whole exome genetic sequencing. But back in 2015 when Dr. Roth and her team began their research, the only known way to isolate those Reed-Sternberg cells was through a process called laser capture microdissection.
Dr. Lisa Roth: Which is literally taking a laser and a microscope and circling around those cells of interest. And that is an effective way of isolating the Reed Sternberg cells, but it's very tedious, it's hours and hours and hours of time and the yield is quite low. Laser capture microdissection might get you one nanogram of DNA. It's not enough Reed Sternberg cells to perform sequencing. It would take decades to be able to do this using laser capture microdissection. At the time whole exome sequencing required 100 nanograms of DNA.
Catherine Price: Dr. Roth and her team knew that laser capture microdissection was never going to yield enough Reed-Sternberg cells to sequence the whole exome… at least not within the next decade. So, they came up with a new approach.
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Dr. Lisa Roth: And that was by not using laser capture [00:08:00] microdissection, but an approach called flow sorting. Flow sorting is an approach to isolate cells using lasers to sort cells into different categories based on the cell surface markers on the cell. This approach is used in many different diagnostic, laboratory tests. It’s used in many different cancer types. It's pretty common. But no one had done it before for Hodgkin lymphoma.
And flow sorting historically has been thought to be not feasible on Hodgkin lymphoma for a variety of reasons. The Hodgkin Reed Sternberg cell has a very distinct appearance under the microscope. The cells are very large, they have very unique surface proteins. Do they even fit through the nozzle of the machine? You know, these are the kind of things that were being considered.
Dr. Lisa Roth: We partnered with Misha Rochelle, who is a hematopathologist who is an expert in flow sorting. And in this partnership, with this tremendous hematopathologist who really kind of pioneered this approach, we were able to do this. And so I think it's kind [00:09:00] of taking an approach of something that others say cannot be done and finding creative ways to be able to do it that allowed this work to happen.
Catherine Price: Through this faster flow sorting process, Dr. Roth and her team were able to isolate more cells, more quickly. But they still couldn’t pull out enough DNA to perform whole exome sequencing.
Dr. Lisa Roth: So if you isolated the Reed Sternberg cells at the time by flow cytometry, you would maybe get 10 nanograms of DNA, but you still needed 100 nanograms. So then we wanted to decrease the amount of DNA that we needed.
So okay, what can we do next to tackle that problem? Maybe we can tweak the way that the platform works to be able to perform exome sequencing with a very low input of DNA. So we created our own custom preparation, called Library Prep, to perform the genetic sequencing on these cells. So then we kind of optimized that workflow so that you didn't need 100 nanograms and you could do this off of 10 nanograms.
By doing this [00:10:00] our group was able to perform the first whole exome sequencing of 10 cases of Hodgkin lymphoma and two cell lines.
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This is the one cancer type where we really have had pretty much minimal understanding of the genetics of the disease and now finally we have an approach that allows us to study the genetics of Hodgkin lymphoma. So this was incredibly exciting for us.
Catherine Price: The team’s findings uncovered how the malignant Reed-Sternberg cells had been evading the body’s immune system. It had to do with a protein that helps the immune system recognize infections: beta 2 microglobulin. The beta 2 microglobulin protein helps the body recognize and fight cancer. But in Reed-Sternberg cells, that protein is missing.
Dr. Lisa Roth: In that whole exome sequencing, 7 out of the 10 tumors had genetic alterations that resulted in loss of beta 2 microglobulin.
And that allows these cells, despite the fact that they have these foreign proteins, to not [00:11:00] be recognized by the immune system. So it's a mechanism that the cancer is using to hide from the immune system. And so understanding the mechanisms by which a tumor cell is evading the immune response can help us to develop these immunotherapies that allow the immune system to overcome that, recognize foreign proteins, and attack cancer cells.
What we can extrapolate is that we need to target the immune response and allow the immune system to recognize these tumors. And if we do that, if the immune system can recognize and attack Reed Sternberg cells, that is a very effective mechanism to clear and eradicate cancer, and especially Hodgkin lymphoma.
We now had an approach that could be used to perform genetic sequencing in Hodgkin lymphoma, which is something that we, you previously just simply could not do. It was really exciting to be able to finally start to get at the genetics of this disease.
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Catherine Price: [00:12:00] But sequencing the whole exome had really only given Dr. Roth and her team a small slice of the overall picture of Hodgkin’s Lymphoma genetics.
Dr. Lisa Roth: Exons are about 1% of the genetic code. So sequencing the exon regions is high yield and important, but you're missing over 90% of the genetic code when you do that. So, the next step was to scale up.
So we were interested in performing exon sequencing on a large number of cases and then whole genome sequencing for the first time in Hodgkin lymphoma.
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Dr. Lisa Roth: When you perform whole genome sequencing, you're sequencing the exons and the introns, and those introns do have genetic alterations that contribute to cancer. So whole genome sequencing can add a whole other layer of understanding to the genetics of the disease. You can also look at genetic signatures.
Understanding the genetic signatures that contribute to Hodgkin lymphoma could be informative about the disease. And that's something that you really want to study genome wide and [00:13:00] not just on the exons.
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Catherine Price: But scaling up to whole genome sequencing to get an even more detailed picture of Hodgkin’s Lymphoma biology meant that Dr. Roth and her team would need more tumor samples. They’d used just 10 samples to perform exome sequencing.
Dr. Lisa Roth: Generally these kind of large scale genetic sequencing projects are done on thousands of tumors. Cancer in general is never the same from person to person. So the more tumors you study from the more individuals, the more precision you have in understanding what are genetic alterations. And some of them will be common and will be shared. Some of them will be more rare, but you need large numbers to have the statistical power to be able to do that. So having a hundred as our goal and our benchmark is where we landed with Hodgkin lymphoma.
Catherine Price: The next challenge? The flow sorting technique they’d pioneered required fresh tumor to perform sequencing.
Dr. Lisa Roth: Flow sorting needs to be done on live cells. So this requires the [00:14:00] tumor biopsy happens, the diagnosis is made that day, and within a day or two you need to be able to sort those Reed Sternberg cells.
And so we were able to do this on a handful of cases here at Weill Cornell and New York-Presbyterian, but we never would have been able to get the number that you need to fully understand the genetic landscape of a disease from just one institution because of this limitation that we needed fresh tissue.
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Dr. Lisa Roth: We reached out through the Children's Oncology Group and through other consortia to develop a consortium of centers that were sending us their Hodgkin lymphoma biopsies fresh.
We didn't know if sending an overnight shipping of fresh biopsy from a Hodgkin lymphoma tumor would yield enough live cells arriving at our center the next day to even be able to perform the flow sorting. So we ran a pilot to just ask that question. Can we receive cases from the outside and can we perform flow sorting on them? [00:15:00]
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Dr. Lisa Roth: And it was a huge success. In fact, the success rate of the flow sorting from the outside cases was as good as our in house cases. And so we said, just keep them coming, like just keep sending them. And over a period of about two years, the center sent us as many Hodgkin lymphoma biopsies as they could.
And we wound up with over 100 cases and over 65 of them passed quality control for whole exome sequencing. And for the very first time we had whole genome sequencing and that was on 20 cases, which was an incredible number for us.
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Catherine Price: By sequencing the whole genome, Dr. Roth and her team were, for the first time, able to fully map the etiology of Hodgkin’s Lymphoma, the timeline that shows how a normal, healthy immune cell turns into a malignant Reed-Sternberg cell. An essential step in developing preventative therapies to treat cancer.
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Dr. Lisa Roth: Cancer is an unfortunate sequence of genetic changes and [00:16:00] understanding the order in which those occur can inform therapeutic options, therapeutic targets, and potentially prevention of disease. So we were able to map out for a Reed Sternberg cell, what is the suspected sequence of events in which these alterations happen? And what does that inform us about when those changes occur that led to the Reed Sternberg cell?
What we found was that large gains in chromosomes, which in other cancers are often the initiating event, were actually later in Hodgkin lymphoma. And that's something that's quite distinct.
Catherine Price: Most lymphomas develop during a normal immune response called the germinal center reaction. It’s when our cells learn how to fight infections…
Dr. Lisa Roth: So that's a normal process in all of us, but when something goes wrong in that process, that's how lymphomas occur. However, for some cases we had evidence that the first genetic change that occurs in Hodgkin’s Lymphoma actually might happen [00:17:00] before the germinal center reaction.
If you can get at this before it transforms into a Reed-Sternberg cell, would that be something that we could use therapeutically? I think that would be. That would be completely transformative for what we do to approach cancer in general.
If you knew that this genetic event gave you a higher risk of developing cancer, and then you can screen for that genetic event and understand which group is more likely to develop cancer, can you monitor for that and then capture those cases earlier on? Or ideally even before they occur.
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Catherine Price: Patients with Hodgkin’s Lymphoma historically have not been able to be included in this targeted approach to cancer therapy because so little was known about the genetics of the disease. But thanks to the tireless work and creative approach of Dr. Roth and her team, that’s no longer the case.
Dr. Lisa Roth: Traditional chemotherapies are like going at cancer with a bazooka. So you're killing the cancer, but you're also harming a lot of normal cells in the process. I think the way that we are moving in Hodgkin lymphoma, and I [00:18:00] think this is absolutely reasonable, is that we are moving away from traditional chemotherapy and towards more targeted therapies.
These targeted therapies are only possible when you have a very deep understanding of the biology of the tumor. But then once you have that, you can develop therapies that go at a specific vulnerability of the cancer cell that's unique to that cell and not to all of those normal cells. So my vision for Hodgkin lymphoma in the future is that we move further and further away from toxic chemotherapy and that we come to an approach that is almost exclusively targeted therapies.
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Dr. Lisa Roth: That's what's so exciting about science is finding creative solutions and new ways of doing things. And then once you have that nailed, it opens up the door to incredible new discoveries that couldn't have happened before. So that’s one of the most exciting things about science.
Catherine Price: The endless problem solving, troubleshooting, and years of research to make treatment safer [00:19:00] and more effective for Hodgkin’s Lymphoma patients is, of course, personal to Dr. Roth. As someone who’s been through treatment herself, she understands the stakes firsthand.
Dr. Lisa Roth: I now see this as a gift that I can offer to patients and their families to hear my perspective as someone who has now been through this and is healthy and thriving. I went on to have two healthy boys, Zachary and Parker. And I think my story and relating that to each patient that I see, it really is a gift.
Catherine Price: Thank you so much to Dr. Lisa Roth for sharing her powerful story with us today. Her tireless work to understand the biology of Hodgkin’s Lymphoma is really changing the way this disease is treated, and leading to more successful outcomes for cancer patients.
I’m Catherine Price.
Advances in Care is a production of NewYork-Presbyterian Hospital. As a reminder, the views shared on this podcast solely reflect the expertise and [00:20:00] experience of our guests. To listen to more episodes of Advances in Care, be sure to follow and subscribe on Apple Podcasts, Spotify, or wherever you get your podcasts. And to learn more about the latest medical innovations from the pioneering physicians at New York Presbyterian, go to nyp.org/advances.
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