Finding Fulfillment in Research and Patient Care

Stephen T Magill, MD, PhD

It all begins with good mentorship, according to Stephen T Magill, MD, PhD, who described that his mentor was his inspiration for entering the arena of meningioma care. Following this inspiration, Magill soon learned that the effect that surgery has for these patients would continue to draw him in, as he was able to see the differences that he was making in patient outcomes.

“For me, as a practicing physician who’s also a neurosurgeon, doing things that are difficult and challenging, and then taking a patient through that, is a rewarding way to spend my time and days,” explained Magill, an assistant professor of neurological surgery at Northwestern University’s Feinberg School of Medicine in Chicago, Illinois.

However, despite his interests in this field, research regarding the treatment of patients with meningioma continues to fall behind that of other tumors within neuro-oncology, such as gliomas. Because of these unmet needs, oncologists continue to launch new areas of research in this space, with the aim of pushing the field forward.

“Seeing where we've gone in the past 10 years and seeing the next 5 or 10 years is going to be exciting,” Magill continued. “It's a great field to be a part of, and I've certainly enjoyed my career and am looking forward to the next 10 years here.

In an interview with Oncology Fellows, Magill detailed his inspirations behind entering not just the neuro-oncology and surgical treatment field, but also the arena of meningioma care and research; provided topline advice for current fellows looking to enter this field; and detailed current and ongoing research in this space taking place at Northwestern Medicine.

Oncology Fellows: What inspires one to go into meningioma care and research?

Magill: A good mentorship is often the trigger in what really starts [this inspiration]. I had a mentor who was interested in meningiomas, and I began with him, and he inspired me. The other thing about meningiomas that I found interesting and that drew me in is the effect that surgery has for the patients. It's one of the primary treatments. Therefore, as surgeon, what I do in the operating room, and surgical excellence, makes a real difference in the patient's outcome.

From the neurosurgical side, that's how I was interested in the way that the surgery affects patient care. Additionally, I have a PhD in molecular neuroscience and as I got interested in meningioma during my residency, I did a postdoctoral fellowship in cancer biology. In my PhD [program], I studied gene regulation, which led me to cancer biology and applying that to meningioma; there is an opportunity from a research standpoint in an [area with] unmet need. This is because meningiomas, or a more benign tumor at least on the surface, is orphaned within neuro-oncology because it doesn't kill you in the next year or 2, like a glioblastoma might. It's also orphaned from a funding and a research standpoint.

When I was coming out [of my program] with clinical interest, there also was a huge unmet need for an application of basic cancer biology, molecular approaches, and opportunity for discovery. It was a bit of mentorship, clinical interest, and research opportunity that all came together and led me there.

How would you say that you have seen this field advance with an improved understanding of the disease biology of meningioma?

Meningioma is an actively evolving and transforming field in several ways. The biggest [way] is in our diagnosis, ability, and understanding of the disease. When I started residency, and before that, medical school, meningioma’s were diagnosed based off H&E [hematoxylin and eosin] slides, sometimes markers, and the grading was based on morphologic counts, and features of that.

Now, we have DNA methylation profiling and we have copy number variants, looking throughout the whole genome. We have genetic risk factors looking at next-generation sequencing, and [we have] now [built] a large understanding from a molecular standpoint. It's not just information, but rather we are learning [that] the biology of the tumor predict[s] much more of what the tumor is going to do. The application of molecular pathology and biological understanding of the disease has completely transformed in the past 10 years.

[These advances] answer a lot of unmet questions in the space. By understanding the biology, we now can better understand whether a tumor is really high risk, even though it might not have met criteria for grade 3 or grade 2. Seeing that applied at the pathological level is really interesting and is different now than it was 10 years ago.

In terms of unmet needs that still exist, what do you think are some things that you'd like to see tackled in the future?

We've just scratched the surface. When you start to understand the biology of a tumor, it gives you some ideas of what we should be targeting. Particularly thinking from an oncology standpoint, no clinical trials have proven effectiveness for meningioma. Therefore, when I talk to my patients, I have no medical therapies for them, which is why it's been orphaned within oncology. All the trials for the [aggressive] tumors that fail radiation and fail chemotherapy, all those patients didn't have anything. Where the biggest unmet need lies is starting to translate what we're learning molecularly into clinical trials and into new targeted therapies.

Some of my research has tried to identify those opportunities and raise ideas. One other interesting thing that's important to understand about meningiomas, is that it is a very heterogeneous disease. When you look at it, there's many different pathological subtypes. Oftentimes, this happens in glioblastoma and other cancers, as patients will just get grouped together despite not knowing what's driving a particular meningioma. As we've started to understand that, and as we're finding biomarkers, the big unmet need is in paired biomarkers, in the biology of the tumor with targeted agents, or with rational therapeutics.

As we stratify meningiomas and start to pair them up, that's where there's a lot of excitement in the field. [This brings forth] a plethora of molecular information, and you can start to get creative and think outside of the box, as well as design investigator-initiated trials. There is a huge opportunity here and a need for neuro-oncologists who are interested in meningioma.

In terms of your ongoing research, can you highlight what you're working on right now?

In one of our recent papers, we looked at a large, international cohort of meningiomas, and performed DNA methylation profiling, and identified different subgroups of meningiomas based on their clinical outcomes. We then went to the lab and identified molecular mechanisms that are important in each subgroup, allowing good outcomes or driving poor outcomes. That was published this past year in Nature Genetics, laying the foundation for some rational targets particularly for the high-grade meningiomas.1 [This also led to] repurposing abemaciclib [Verzenio], which is a CDK4/6 inhibitor that's been used in breast cancer, and it suggests that may have a role [in meningiomas].

What I'm most excited about that's going on and not yet out now, is the development of molecular biomarkers that can stratify patient decision making. There are 2 clinical trials ongoing for grade 2 meningiomas on whether we should do adjuvant radiotherapy. As a bit of background, in grade 1 meningioma, typically the oncologist will take it all out if possible. If there's residual disease, it can be watched and if it grows, we can radiate it. However, in grade 2 meningiomas, if you remove them and there's residual disease, it is agreed that you should radiate, and same for grade 3. Notably, if you take out all of a grade 2 meningioma and do a gross total resection, there's [discussion] about whether or not to give adjuvant radiotherapy.

There are randomized trials going on, one through NRG Oncology, that randomly assigns patients to 6 weeks of cytotoxic radiation vs just observation, which is amazing. [The trial is enrolling patients with] grade 2 [disease] that underwent gross total resection. Using the cohort that we had developed of 565 meningiomas, we looked at our data from the DNA methylation profiling and RNA sequencing that we had done, and then identified a gene expression risk score that puts patients at either high or low risk. We identified a risk prediction score based off this gene expression panel that can identify patients who would respond and benefit from radiotherapy. The revisions for that are under review at Nature Medicine. What this gene panel will do is gives us some data, at least based on retrospective cohorts.

We now have patients from 12 countries and over 800 meningiomas in the revision, and we have multiple collaborators. They all came together and contributed to our data. We're using that risk score to identify patients who would benefit from radiation. Moving forward, we'll want to validate that prospectively.

In meningioma, the time course of the disease is 5 to 10 years. If you have a disease where the median survival is 18 months, you can run a prospective trial to get some answers and keep turning it over. However, when there is a 50% recurrence rate at 5 years, as with a grade 2 meningioma, it's harder to run those trials in a way that provides meaningful data. I'm excited because I think the more we can molecularly profile the tumor, get gene expression risk score, and then start to follow our patients prospectively to provide rational therapy, this will allow us to provide more precise care.

This has been done with other gene panels, such as Oncotype DX in breast cancer. To do that, in meningioma where we previously had nothing is making it intellectually interesting as a fellow or provider interested in the field, and terrific as a clinician, as we have something to offer the patients. This makes sense to try this or to set up a trial to ask those questions.

What are some of the molecular aberrations that have been identified in retrospective analyses?

For the molecular profiles, what we've discovered in using methylation, is that there's 3 different subgroups that don't perfectly fit with grade 1, 2, and 3, but are a stronger prediction of clinical outcomes. The gene expression panel that we've developed, now goes beyond that and puts patients into high-, medium- and low-risk categories. Our group, along with some of our collaborators, have found several high-risk markers. The loss of chromosome 1p seems to be either an early transformative event, or a major driver of recurrence and growth in the more aggressive [tumors]. Another gene is chromosome 9p, and when that is lost, you can lose CDKN2A/B. Homozygous loss of that makes a meningioma grade 3. Even if you look at the tumor under the microscope, if a patient has that molecular characteristic, they are automatically grade 3, as we know that's the highest risk. Those are probably the 2 strongest things that we can see very easily and are more translatable. Many places can test for 1p loss because of the importance of that in oligodendroglioma, where it has a more favorable outcome relative to other gliomas.

Are there certain trials that you’re excited about and looking to enroll to at your institution?

We've been a participant in the Alliance trial, which has multiple arms trying to look at different targeted therapeutics. There's still 1 arm open here for MAPK inhibitors, and the mTOR pathway. We are still waiting for the results of the abemaciclib arm, and we're excited for that.

However, of the more exciting and innovative trials that we have here is one from one of our neuro-oncologists who is doing an investigator-initiated trial [NCT02847559]. The trial is combining tumor treating fields [TTFields], which have been used in glioblastoma, along with bevacizumab [Avastin] to see if that would provide benefit for recurrent meningiomas. The background of that is very interesting because in some patients who had gliomas, they would [also] have a meningioma. As you followed these patients, and they got TTFields for their glioblastoma, the meningioma started to shrink. Therefore, investigators put together this investigator-initiated trial, and we're excited to offer that as a totally different modality.

When you think about treating [patients with these] diseases, you can [use] a certain inhibitor, and then try a different one or [one that targets] a different spot in the pathway, as well as a broader chemotherapeutic. However, this is a totally different mechanism and I'm excited to see the results of that. This is ongoing so if patients wanted to come here, we have that available.

We also have the [phase 3] NRG BN009 trial [NCT04588246] that randomly assigns patients to radiation or not. The one I'm most excited about is the TTFields trial though, to see what that does.

What advice would you offer oncology fellows who are looking to either specialize in meningiomas, or the larger neuro-oncology field?

Going back to the beginning of how I became interested in meningioma, and for me, as a surgeon, it was developing my surgical skills, particularly for the difficult meningiomas, and really getting involved, [that helped me] understand and start to do research. Neuro-oncology is a rapidly evolving field, no matter what specialty you are in, which is why oncology and neuro-oncology are fascinating. To do that, you have to stay up to date with the reading, understand how to critique a paper, and understand when you can generalize to your patients or not.

However, how do you stay up to date on the latest things? The best way, in my own experience is by doing the research. Being involved, even in clinical outcomes or clinical trials, [is important] and you just have to get in and start participating. Seeking out any of those opportunities will build your skill set, build your career, your CV, and let you be in a place where you can make a difference for patients with your ideas, your curiosity, and your insights. If you don't get in and do it [yourself], then you will be a bystander. There's a difference when you're teaching it vs when you're creating that data, in how you understand it.

To all the fellows, especially when you're in training, maybe you want to be in practice, which is terrific. We need good oncologists everywhere that are fully focused on [being] excellent clinicians. However, that experience while you're a fellow will build skills that then you can apply as a practicing clinician to stay up to date and be able to incorporate the latest data in your practice. If you do that, seeking out neuro-oncology roles, a lot of that depends on opportunities. There's great fellowships for it. For example, you can come to our fellowship at Northwestern Medicine. I interviewed our fellowship candidates for this year, and there's terrific people. We really need a lot of thoughtful people, and creative people in this field.

In the past, neuro-oncology was looked at as not as exciting or interesting compared with other cancers, especially like hematology where things turned over faster as far as discovery and application of targeted therapies. However, if you look at what's happening, this is a perfect time to dive into the field. Within neuro-oncology, if you have an interest in meningioma, there's a lot of lower hanging fruit, which is how I got into this and applied the molecular background, and I have really enjoyed it.

What do you love about being able to work in this field?

One of the best parts of being a surgical neuro-oncologist, as well as for an oncology fellow, is that we work in teams. It's really a vibrant, interactive specialty. [This space] beings in many people, even beyond fellows, including research coordinators, research nurses, and advanced care practitioners. From the physician side, thoughtful neurosurgeons, oncologists, radiation oncologists, pediatrics, and other specialties [are also important] and there's a huge need for them. It's a wonderful community, and we impact people at important places in their lives. It's a great community, as far as your professional interactions, and your day-to-day is stimulating and interesting.

Ten years from now, as we study the biology, we [may] be able to see how we can apply the discoveries that we're doing in the lab to novel therapies. We're working on some research in vivo in mice with polymers that break down and deliver drugs locally. Seeing [this research continue] will be [important].

What is important to remember about your role relative to other advocates in the health system?

One final thought, especially for oncology fellows, is never to underestimate the importance of patient advocates, and our patient organizations. They're powerful in empowering our patients to understand their disease. As providers or wherever your role is in the care [continuum], to interact with those organizations is valuable. To help promote philanthropy [is also important]. A lot of the work that I did in meningioma was initially funded by a large philanthropic grant from a grateful patient, and that was transformative. We couldn't have gotten NIH [National Institutes of Health] funding or my postdoctoral fellowship grant if we didn't have that seed money to start this project. Therefore, doing everything we can to share the need with people who are in a position to make a difference in the field philanthropically is super important. We are really empowered by grateful patients, philanthropic organizations, and helping patients go through this really difficult time in their life.

Reference

Choudhury A, Magill ST, Eaton CD, et al. Meningioma DNA methylation groups identify biological drivers and therapeutic vulnerabilities. Nat Genet. 2022;54(5):649-659. doi:10.1038/s41588-022-01061-8