Mark Moran [00:00:04] Hello, welcome to TGenn Talks. I'm Mark Moran. Hearing the words you have cancer comes as a shock. Hearing that your child has cancer is almost unimaginable. And when you learn that it is a rare form of brainstem cancer known as diffuse intrinsic pontine glioma or DIPG, that affects less than 300 children per year, the questions become endless. Brain tumors are now the most common cancer and cause of cancer related death in children. Less than 15 years of age today, with DIPG accounting for nearly 80 percent of all brain stem cancer cases die. DIPG is a central nervous system, cancer that forms from glial, the supportive tissue of the brain and spinal cord. The average survival time following diagnosis is about a year.
Mark Moran [00:01:00] Joining us today on TGen Talks is Dr. Michael Berens, professor and director of TGen's Cancer and Cell Biology Division and head of the Glioma Research Laboratory, who leads to DIPG research efforts. Those are focused on conducting genomic profiling of tumors to increase the understanding of DIPG at the genomic level and developing techniques to monitor how tumors are responding to treatment. Dr. Berens, welcome. Thanks for being here.
Dr. Michael Berens [00:01:30] Mark, I'm thrilled to be here with you.
Mark Moran [00:01:32] Genomic research has helped advance diagnosis and treatment of a number of diseases. Do you hold the same hope for DIPG and if so, why?
Dr. Michael Berens [00:01:41] Well, I do hold very high hope for the utility of genomic analysis of DIPG. And the reason behind that hope is that the more we interrogate and understand the mis wiring of the blueprint that causes the cancer, the more likely we're going to be able to design better treatments or to stratify patients in ways that we can put to work the best treatment for individual patients today while new treatments are being developed. So my enthusiasm and my hope are both very high.
Mark Moran [00:02:20] How does DIPG form, what effect does the tumor have on the patient?
Dr. Michael Berens [00:02:26] The cause of DIPG is poorly understood. There's a general sense that something goes wrong in the cells differentiating into the fully mature cell type they're designed to become and they get arrested. It's a differentiation arrest. They're immature and they keep growing when the other normal cells mature and stop dividing. So we're not we're not exactly sure how that loss of differentiation takes place, but we haven't been able to link it to a specific environmental exposure. It doesn't at all appear that DIPG is an inherited form of cancer so the kids don't get it from their parents because of their parents' genetics. It seems to be a sporadic, terrible, but fortunately infrequent type of cancer. Quite a mystery scenario of intense study. I've been excited in the last decade to see so many more labs now build up research programs studying this rare form and currently poorly treated disease.
Mark Moran [00:03:34] With it being so rare, we mentioned less than 300 cases per year. How do you recognize it? How does the patient present and how do you know how to test for that?
Dr. Michael Berens [00:03:45] The tumor DIPG forms in an anatomical structure in the brain called the Pons. So when you say diffuse intrinsic pontine glioma, the Pontin label means it forms in this structure in the pons. The brainstem is where all the communication from the brain up above passes through to control all the functions in the body that are regulated by the nervous system. So the symptoms or the manifestations of a child developing DIPG show up as changes in nervous system function. So lots of coordination, speech problems, balance issues, visual problems will show up that way. So these are the kind of symptoms that show up when a child presents, then the caregiving team will recommend. Let's take a look at what's happening in the brain. They'll use modern medical imaging technology MRI to look at the brain. And the difference in the tissue of DIPG is markedly distinct from normal brain. And the anatomical obstruction becomes really clear that unfortunately, then the doctor says we think we know what's going on here, your child has a tumor in their pons. That's typically how these present.
Mark Moran [00:05:09] so while, rare, fairly easy to spot when you do spot one when you do find one?
Dr. Michael Berens [00:05:15] Correct. The tumor roars out and the child suffers physical manifestations and a change in neurological behavior. And then medical imaging is fairly accurate to say we we have a beast to deal with.
Mark Moran [00:05:31] How have you utilized genomics to understand DIPG and develop some potential treatments for it?
Dr. Michael Berens [00:05:37] So genomics lets us look at how the genetic information, which is in every cell in our body, it lets us look at how that information is unpacked and being used for a cell to do things. So certain genes are unpacked and used in heart cells, which makes those cells shrink about once a second. That's why our resting heart rate is around 60 beats per minute as adults, because the genetic wiring leads to some very specific behavior. Those cells, when we look at the genomics of a DIPG cell, we can see that they're not a lot of genetic mistakes or mutations that show up. But one very common mutation shows up in the gene. The instructions of which allow a cell to make a protein that the DNA wraps around when the DNA is parked and protected from being used. So it's a fascinating story about kind of a mechanical gene that it's just a it's like a box. The DNA gets wrapped around to protect the DNA so it doesn't get damaged in the course of just normal events, but that DNA gets unpacked. So the genes that are on that strand of DNA can be used for the cell to behave. When there's mutations in these proteins, they're called histones. There's one very specific histone and one very specific site on this histone that shows up invariably in DIPG. So it's amazing how precise the molecular pathology can be, which is a bit staggering because one simple mutation on a packaging protein leads to this constellation of bad behavior in these cells that becomes malignant and life-threatening to these kids. So our understanding of the disease has soared. We've also seen that while this 27 mutation in DIPG tumors is common, common, common in this rare tumor type, we also see that the accompanying other mutations is extremely variable. So on the one hand we think, oh, there's a trigger, a single trigger that leads to the disease. But then all these other changes in tumor suppressor genes that hold back tumor growth or onco genes that tend to, when they're mutated, push cells to become cancer cells, we get these other constellation of changes that are exquisitely variable, patient to patient.
Mark Moran [00:08:22] Dr. Berens, how does TGen's research into DIPG differ from other studies and are there certain vulnerabilities in that specificity, what you just described, that you're able to attack in trying to cure this?
Dr. Michael Berens [00:08:36] What's distinct about any specific cancer research project is that we end up whether we're studying adult brain tumors or tumors in the pancreas or colon or breast cancer, lung cancer. When we focus in on a tumor in a specific anatomical location, there are what the community refers to as smoking guns, that we see these highly likely culprits and we try to go after those with specific therapies. In the case of DIPG, this histone mutation is a very unusual mutation and it makes a very curious therapeutic target. So like, well, if that's the problem, why don't we turn off the behavior of that gene? Then the real challenge there is we need histone proteins in our cells to package the DNA, protect it, and then unpack it when genes need to be turned on. So you can't really turn off the gene. So can we fix the mutation? There's a big effort to say, well, if you can fix the mutation, would that cause the cells to stop behaving as if they were malignant? The answer is probably not successful because there have been whatever that histone mutation has caused. Among those are these other mutations in other genes. But it's still worth a hard try to say, can we reverse that? And we're excited. To put energy into understanding, how can we try to turn back that one misbehaving gene and see how profound an influence it could have on regaining some control in the cells?
Mark Moran [00:10:12] You're listening to TGen Talks. I'm Mark Moran. Joining us today is Dr. Michael Berens, professor and director of TGen's Cancer and Cell Biology Division and head of the Glioma Research Laboratory, who leads to TGen's DIPG research efforts. Dr. Beren's, your work is supported by a number of families who've lost children to DIPG. Does that add an extra sense of "man, I really need to get this right" to your work?
Dr. Michael Berens [00:10:39] Well, there's something about a child that's afflicted with cancer that pulls on your heart as well as your mind, really on your soul, that this sense of victimhood, the young innocence, it seems like such a violation of all the hopes and dreams that a family has that are inescapable with a new life come crashing, especially with a dire prognosis that often accompanies DIPG. So we we do want to move with a sense of urgency and at the same time we have to be careful. We don't want to move ahead prematurely and potentially create harm instead of help. There is that tension that plays in that space. The other arresting component is we've mentioned how different the tumors are from child to child to child, even though they may all share this histone mutation, the other manifestations of the disease make us move slow like well with this work in this child. And so being able to work in a precise, customized manner on a patient by patient basis is a big challenge. But we definitely feel the pressure for this working closely with families. And TGen actually reaches out to the families twice a year. We host a scientific update. We held one this past week. We had families connect with us and wanting to hear what are the efforts that are moving forward. Many of these families teach and had sequenced the tumor from their child who had passed away. And we do privately meet with those families and we get to share with them. Here's what we learned about this disease because of your courageous gift to provide us tumor tissue to help understand the disease process. And I've been stunned over the last five years how with each tumor we get to look at, we learned something about the disease that we frankly didn't know. Recently, we met with a family whose child passed away from DIPG. We had three different samples of the tumor and it was as if it was three different tumors. And we found a gene that was very active in one of the tumor samples and not the other two that that gene had not been described in association with a cancer previously. So we we learned about a new gene that can misbehave and contribute to cancer. Those kinds of discoveries have very real possibilities of opening up new opportunities potentially for treatment. And we just get so excited and grateful for the courage of these families to say we want to be part of it. Those families who've lost a child, they've chosen not to run away in grief, but they've decided to stay in the fight and they encourage us. They connect with us twice a year. Some of them raise funds to help advance our research efforts. These are incredible heroes who we love being held accountable for. Where are we going? What are we doing? Who are the people that are involved? So I counted an enormous privilege to work with these families that are, frankly, the backbone and the wherewithal of us being able to do our research.
Mark Moran [00:14:05] And maybe in some small way they feel a connection still with the child they lost through you.
Dr. Michael Berens [00:14:11] Well, maybe it's more us with them. I have to say that we typically don't have tears at my lab meetings, but when we review some of the DIPG tumors in our lab meetings, it's been interesting since we've been meeting with these families, those now become not just scientifically driven, but we do become more emotional because of the family connections. That's why I phrase it. You know, it's our connection with them and with their children. We know names because they're very vocal about this. It makes that not just a piece of tissue that we're studying. We see that, in fact, it's a life. It's a lost life. It's a life that had potential that was stolen. We do push really hard in that space.
Mark Moran [00:14:55] Where is the research headed and what do you think it will take to get there?
Dr. Michael Berens [00:14:59] What I'm most excited about is our liquid biopsy program, where as therapies are developed, it's helpful for the oncologist to know is what I'm doing today beneficial for the patient in my clinic? And so having a liquid biopsy that gives a real-time assessment of what's happening in the tumor tells the oncologist, stay the course. It looks like the tumor is staying under control or it looks like the tumor is escaping therapy. We need to look at something else. When I get feedback from the actual doctors caring for the patients, they are so eager for that kind of feedback. And medical imaging is helpful. But in the context of brain tumors, there are so many other events that happen, tumor swelling, inflammation that may be going on that it's difficult by medical imaging to be very confident that I can see what's happening to the tumor. I know they can see what's happening to the brain, but interpreting it as to are we actually hurting the tumor or are we causing inflammation, it's a very difficult challenge. And so having a liquid biopsy, that is a readout, almost a digital readout on how much tumor is the patient dealing with today compared to two weeks ago? Wow, that kind of feedback excites me to no end. The other thing that I'll say that we're doing at TGen is we're touching on a technology that many labs around the country and around the world are working on. And that is how do you get a drug to a brain tumor? The brain is wrapped and perfused with blood, but the blood vessels have a distinct anatomical structure that we call a blood brain barrier. It keeps any toxins that are in our blood from getting into the brain, which would be a really bad event. So it protects the brain from those toxins, but it also protects the brain from any therapy that a patient would take orally or even intravenously as an infusion. The drugs have to get across the blood brain barrier, so that creates a problem when you can't deliver it. And there are actually no very effective therapies that can hurt. Brain tumor cells, but if you can't get it to the tumor, it's a total frustration. So we're working with a team of engineers and bioengineers to study the blood brain barrier. How do we open it? We may be right at the cusp now of seeing in the next coming year or so of ultrasound guided opening of the blood brain barrier, very specific where the tumor is to get effective drugs into the brain. There's going to be some very exciting work, I believe, coming from that effort.
Mark Moran [00:17:35] How can donors or potential donors get involved?
Dr. Michael Berens [00:17:39] We would put resources to work today if we had more resources. TGen is so fortunate to have an exquisite team of compassionate discipline support personnel in the TGen Foundation. And they would love to dialog with people or I'll connect with folks and talk about our science. But that dedicated team is there to help if folks want to get involved in supporting our research.
Mark Moran [00:18:04] I know that you are a fan of the phrase most best days when you talk about DIPG, what does that mean?
Dr. Michael Berens [00:18:11] So I'm doing DIPG research in part because of a very close encounter with a family that my wife and I got to know whose little child Hollis was taken to hospital here in Phoenix. Phoenix Children's Hospital with some of these neurological problems that had manifest and got progressively worse and MRI indicated Hollis had a pontine glioma. My wife was working as a chaplain at the time at Phoenix Children's. She called me from Hollis's hospital room and said, Mike, can you talk to Hollis's parents? Thomas has just been diagnosed with the DIPG. The crisis for parents of underage children is all the treatment plans for their child need to be consented to by the parents. Shane and Shawn were at wit's end, like they're posing all these treatment options, surgery, radiation, proton beams, traveling to other clinics. And their struggle was how do we know what to do? Are not the doctors is spontaneously. I told Shane and Shawn that you're being asked to make a decision because you're actually the most qualified, just like you've been making loving, caring Forward-Looking decisions on Hollis's behalf for his whole life. Those are the same motivations and practices that you want to put to work for us now that you're dealing with a very different scenario. But it's still that loving, caring, forward looking gesture. So I encourage Shane and Shawn to use as a metric this most best days that only Shane and Shawn could decide for them as a family what those parameters were. And they found enormous comfort and encouragement around that in dealing with these very difficult personal and yet life-altering decisions. So that's sort of become a slogan around how I look at DIPG. Let's make decisions in real-time right now because we're dealing with these while we keep a long-sided view about breakthroughs in understanding the disease, hopefully prospects in new therapies that we want to be part of. Meanwhile, today we have to be making some of these hard decisions and most best days serves as a pretty helpful parameter to hold on to.
Mark Moran [00:20:41] Some incredibly important research into this very difficult field. It's been a good day for us, Dr Berens, in terms of learning, thanks so much for sharing with us today.
Dr. Michael Berens [00:20:52] Absolutely. My pleasure. And there's hope. There's real hope. That we're pushing on the boundaries here.
Mark Moran [00:21:00] That's Dr. Michael Berens, professor and director of TGen's Cancer and Cell Biology Division, leading the charge against DIPG. May 17th is DIPG Awareness Day. Look for social media posts from TGen and please plan to repost and help raise public awareness of this deadly childhood brain cancer. Please help us spread the word. To hear more TGen Talks, visit TGen.org/tgentalks. TGen is an affiliate of City of Hope. Thanks for listening. I'm Mark Moran.