Pediatric oncologist’s work on NF1 condition earns Sammies nod

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No one likes to see a child in pain because of a permanent and useless condition. But Dr. Brigitte Widemann was able to do something about the terrible condition known as neurofibromatosis type 1. She is the chief of pediatric oncology at the National Cancer Institute and a finalist in this year’s Service to America Medals program. Widemann joined Federal Drive with Tom Temin to explain her work.

Tom Tem: dr. Widemann, good to have you here

dr. Brigitte Widemann: Thank you very much, Tom. I’m also very happy to be there, and you did a great job. Neurofibromatosis type one, and its abbreviation is NF1. That’s what you usually call it, because it’s quite complicated.

Tom Tem: Certainly. And tell us more about the disease itself. What does it do and what is its history?

dr. Brigitte Widemann: So NF1 is a condition that is inherited, it is passed on from parents to children, or it can occur spontaneously, but it is caused by a genetic change in the gene called the NF1 gene. And when this genetic change is present, it is present in every cell of a patient’s body and can cause many different types of manifestations, including tumors that I have focused on developing treatments for the so-called plexiform neurofibromas. These tumors, while not cancerous tumors, can become very debilitating by disfiguring, causing pain, causing deterioration and airway function and bowel and bladder function. And one aspect that was really important to me is that they develop in very young children and grow quite relentlessly during early childhood. And NF can cause many other manifestations and problems, but this is the one I’ve focused on working on to see if we can develop effective treatments to stop these tumors from growing or potentially shrinking.

Tom Tem: And do we have any idea how many people per year have this kind of effect?

dr. Brigitte Widemann: Yes we do. So about one in 3000 people has inner neurofibromatosis type one, so it’s not that rare. And of the people who have enough fun, about 50% can have this particular trauma called plexiform neurofibroma. While not all of these tumors become severely debilitating, a subset of these tumors clearly and most often do during early childhood.

Tom Tem: And you’ve developed a methodology to explore this to try and get to what you suspected might be something that could reduce it. Tell us the methodology there?.

dr. Brigitte Widemann: So that’s a great question. If you look at clinical trials of drugs for cancer patients, the cancer tumors usually grow quite quickly. And we can tell in four to eight to 12 weeks whether a drug is working or not. If we were to use the same kind of measurements as with cancer tumors, we wouldn’t be able to say whether the drug works in NF1, because the tumors consume much more slowly. So we developed a method called volumetric analysis, where we measure tumor volume, and that allows us to determine much faster whether tumors are growing or shrinking. And this was very helpful in the clinical trials I was designing back then with new drugs to see if they would help my patients.

Tom Tem: And the measurement wasn’t something you could do in a few months. This was 10 years of work. Correct?

dr. Brigitte Widemann: Actually yes. So the measurements we started with more than 10 years ago. And now that you bring this up, we’ve really learned through that method how tumors grow when patients don’t have an effective drug. And once we found an effective drug, the Food and Drug Administration, which then approved the drug, they wanted to see data on what it looks like in patients who aren’t getting treatment. And so we have these 10 years of data to send to the FDA and they could clearly see, yes, this new drug is different and changes the natural history of the course of the disease.

Tom Tem: And there was an existing drug that you suspected might help here, I believe it was called selumetinib, and it had failed to treat breast cancer. And what gave you the clue that it might work for NF1 in this particular situation?

dr. Brigitte Widemann: Yes,. So we had done some clinical trials. One thing that’s important in NF1, when it’s mutated, the genetic changes there, it results in upregulation of a pathway called grass toad, which is mutated in many adult cancers and upregulated in many cancers. So when I saw a drug being used in cancers, even though it didn’t work in cancers, I still hoped that given that this tumor I’m treating isn’t a cancerous tumor, it might work. And we’ve done some studies that focused on other components of this pathway, with no success, so that narrowed it down to this particular drug called selumetinib.

Tom Tem: We speak with Dr. Brigitte Widemann, she is a senior investigator and chief of the Division of Pediatric Oncology at the National Cancer Institute, and a finalist of this year’s Service to America Medals program. And there’s an emotional content to dealing with really bad kids and their families by extension. Any specific cases that stand out to you and that you would like to say to yourself, I want to help this child.

dr. Brigitte Widemann: Yes definitely. The patients were so great Tom. I have patients who may have undergone five or six different clinical trials without any positive effect on tumor shrinkage. One of these guys seeing he was almost 18 when he started the selumetinib and first too much rain. These are emotional ones indeed and these are victories that we celebrate with our patients. But yes, pain, as you said before, is really important, the pain can be debilitating. So having something that can improve pain is hugely helpful. But also reducing deformities and allowing patients to function more effectively. When patients see that their clothes fit again, or they can go to a store and buy regular clothes, or when they see that they can struggle with their sibling, which they may not have been able to do before. Those are very happy moments indeed. And we’d like to do a lot more for our patients, but it’s progress.

Tom Tem: Agree. And so the progress is that you found that this drug that wasn’t effective elsewhere is actually shrinking the tumors to a decent amount.

dr. Brigitte Widemann: Yes, it shrinks the tumors and also prevents them from growing. And so we didn’t see the tumor disappear completely. As I said, it stops the tumors from growing and shrinking them, which helps the patients and provides clinical benefit. One thing that we’re doing now that I’m really, really excited about, and we’re hoping to start treatment earlier in younger kids with these tumors before they get really debilitating, so hopefully we can actually prevent the development of these problems.

Tom Tem: Okay, and we should point out, this isn’t your only job at the NCI.

dr. Brigitte Widemann: No, I do other things. So one area I’m very involved in is applying lessons learned from NF1 to other rare tumors. There are many rare tumors in children and adults for which we have no effective therapy. For example, we have an active program for children and adults with rare tumors. And then I’m also the head of the pediatric oncology department, overseeing a wonderful group of colleagues, both with fundamental research interests, translational and clinical research interests. And our overall goal is to make better treatments for children with cancer,

Tom Tem: And the clinical trials that we’ve described and some of the others that the NCI is doing are the patients at the NIH itself, or are they doing this remotely?

dr. Brigitte Widemann: For most of the clinical trials that we have, all the treatment trials, the patients come to the NIH, they get their treatment at home every day, but they come in through the NIH to be started. And then we take them back to the NIH to see if the drug is working and what the side effects are. With a COVID pandemic, we are loosening up and patients can do more things at home. And for some studies, patients can enroll remotely from home.

Tom Tem: And briefly, what is your background? Why did you choose a research career in oncology and at the NIH of all places?

dr. Brigitte Widemann: I got my education, I’m from Germany, and I did my pediatric resident education there, and really wanted to study oncology and then learned that there was a fellowship program at the NIH, something we didn’t have at the time. had in Germany. And what really intrigued me was the closeness of the couch to the bed, the ability to do clinical research, and I’ve never regretted coming here. It is the best place to do clinical research and advanced therapies for children.

Tom Tem: dr. Brigitte Widemann is a senior investigator and chief of the Division of Pediatric Oncology at the National Cancer Institute. Thank you so much for coming to me.

dr. Brigitte Widemann: Thank you so much for having me. Good day.

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