Professor of Neurosurgery at Johns Hopkins School of Medicine, Chetan Bettegowda, MD, PhD talks about a cerebrospinal fluid to find cancer.
Interview conducted by Ivanhoe Broadcast News in 2023.
Twenty-five years looking into neurosurgery, the brain, the spine, everything that goes with it, tell us about the cerebrospinal breakthrough.
Bettegowda: Absolutely. So cerebrospinal fluid is the water, the fluid that bathes the brain and the spinal cord. It’s normal, we all have it. It’s continually produced by the body, every day, every hour, every minute. One of the challenges in neurosurgery and my particular specialty is neuro-oncology, or surgeries involving tumors of the brain and spinal cord, is understanding what’s happening in the brain without having to do invasive surgeries like biopsies or actual resections. What our group has been focused on is trying to identify minimally invasive ways of studying the tumor with actually not sampling it. So these are generally coined liquid biopsies, meaning we’re interrogating the blood or in this case the cerebral spinal fluid to gain information about what’s happening in a brain or spinal cord, tumor or cancer.
So in a generalized way, you’re examining through liquid biopsy, the cerebrospinal fluid. In a specific way, how does that turn from that generalized sample specifically, here’s tumor A and tumor B?
Bettegowda: Great question. So what we do in analyzing the cerebrospinal fluid is to look for markers that are specific for a cancer cell. The approach we’re taking is to look at alterations at the DNA level. So we know that one of the hallmarks of cancer is that they contain mutations or changes in the DNA that are not found at appreciable levels in normal healthy brain or any other cells. And the specific type of alteration we’re looking at is called aneuploidy. Meaning that when we’re born, we typically get a normal complement of DNA from mom, normal complement from dad to make one healthy cell. Cancer cells lose the ability to maintain this normal number of chromosomes. Sometimes they gain fragments, sometimes they lose fragments and they rearrange fragments and it’s oftentimes very complex. But all these changes in fact end up helping to drive the cancer process. And this is called aneuploidy, the sense of global changes to the chromosomal copy number that should be normal, becomes abnormal or deranged in almost all cancers involving the human body. And what we’ve done with the help of Dr. Douville and others at the Ludwig Center at Johns Hopkins, is to be able to harness these findings, this biological phenomenon that cancer cells have abnormal copy numbers. To be able to identify fragments of DNA shed by brain cancers into the cerebral spinal fluid, and uniquely identify it from the normal DNA, that normal cells are shedding. So in folks who have cancer we’re able to say, wallah, we’re seeing these abnormal chromosomes suggestive of cancer and within the cancer is perhaps suggestive of one type over another. In individuals who have a different process, like an inflammatory process or an infectious process, we don’t see that and so one day the goal is to be able to say, for an individual who has a neurological problem, a finding on a brain scan, like an MRI scan, to be able to do this minimally invasive test and say we think there’s a very high likelihood that there’s a cancerous process or very low likelihood that there’s a cancerous process, then hopefully allow them to triage into appropriate next steps.
How do you then pinpoint the location of that? Is that done through another diagnostic tool like a CT or MRI?
Bettegowda: So indeed the brain, for better or worse, is an organ that can have cancers from all over the body. It’s one of the most common sites for what we call metastases, meaning spread of a cancer from another organ to the brain. In addition, we know the brain itself, unfortunately, is capable of having cancers that start and originate in the brain called primary brain cancers. And so this test has the ability to both detect primary and metastatic cancers of the brain. And depending on the specific types of alterations at the DNA level, we can get clues as to potentially what type of specific cancer it might be. But ultimately, that definitive diagnosis is done through additional imaging. And eventually, in most cases, a definitive biopsy with the tissue sample being performed.
How cutting-edge is this compared to previous diagnostic methods?
Bettegowda: So we really think this is an important leap, not just an incremental one, but potentially a profound one to help our patients with neurological findings. Historically, there have been no biomarkers, no blood test, no CSF tests that have been shown to be very effective in diagnosing these cancers. The current goal standard is to take the cerebral spinal fluid and put it through a machine that helps to identify the presence of cancer cells. This is through flow cytometry and cytology and unfortunately, depending on the type of cancer, it may be able to detect it in 50% of cases, 25% of cases, or even less. So unfortunately, the existing technologies are just not good enough to be able to help the majority of our patients with brain cancers. In our study, we’re able to detect 70+% or more of cancers depending on the subtype. So we think this is a huge advancement, but we think is the first step in ultimately being able to create a technology that identifies the vast majority of brain cancers and that’s the type of work that we’re working on currently.
There’s always a long timeline associated with any breakthrough. Where is this on the timeline of every type of FDA approval?
Bettegowda: Obviously, having a research paper is of importance, but the true impact is only measured when we’re able to get these technologies to patients. We’re hopeful that by appropriately partnering with collaborating institutions and organizations that this and similar technologies can be available for patients in the next 12, maybe 24 months.
That’s fast.
Bettegowda: It is fast.
That’s an aggressive goal there. How did you set that?
Bettegowda: So it’s through partnership. This technology was developed at Johns Hopkins and this technology has been licensed with a commercial partner who is attempting to bring analogous approaches into the clinics and we know that this is a huge need. Metastatic brain cancer affects over 200,000 individuals in the United States a year to the brain. Primary brain cancers another 30,000 -50,000 depending on the specific subtypes. So we’re talking about tens of thousands of individuals every year in the United States for which there’s no existing way to study or monitor without actual tissue biopsy. When you think about biopsy, can there be a more difficult or dangerous area to biopsy in the body than the brain? I’d hazard to guess probably not many. And if we’re able to have a technology that can help identify and potentially preclude some subset of these individuals from having to undergo a risky or invasive and expensive, cumbersome procedure, then we think that’s something that needs to be tested rigorously and hopefully brought to the clinical realm as soon as possible. And so we have fortune to be able to collaborate with folks who share that vision of helping individuals with brain cancer. The goal is ambitious. We can try, but if we fail trying our best, I can live with that.
Are you doing a needle biopsy under the spinal fluid or how does that process work?
Bettegowda: So the way the CSF is obtained is very common part of clinical practice has been done for decades, is typically through what’s called a spinal tap or a lumbar puncture very similar to when women undergo epidural anesthesia during labor and delivery. Small needle is introduced in the back, it is pushed a little further in than when an epidural anesthesia is obtained in order to identify where the CSF is in the low back. It’s often done right now under local sedation or with CT or X-ray guidance to make it less painful. Procedure typically lasts a few minutes and approximately 2-3 mls of cerebrospinal fluid, which is less than a tablespoon is what’s required for the test that we studied. And then from there, it’s sent to a laboratory for a series of experimental set ups and analyses to be able to give us this understanding of if there’s these aberrant chromosomes present within that sample.
You hear a lot about glioblastoma being so deadly and so quickly acting very aggressive. So when you get this liquid biopsy, would that distinguishes this as compared with this?
Bettegowda: That is the ultimate goal is indeed that if someone has a glioblastoma either at the time of diagnosis and we don’t know what it is that this can help aid and say, yes, indeed we think this is what it is. Perhaps we can move forward with definitive treatment, or perhaps direct them towards urgent surgery, or in a more common scenario, which is they have a diagnosis of cancer already, whether it’s glioblastoma or others and they’re undergoing treatment. And we know that treatments like radiation therapy, or chemotherapy, or immune therapy can actually cause changes to an MRI scan. And that these changes on the MRI scan can be equivocal, meaning it’s not clear whether it’s the cancer coming back versus the effect of the treatment. And so sometimes as neurosurgeons, we have to go in to remove or sample that abnormal tissue to help discern, to help identify, is this cancer recurrence or is this treatment effect? The hope is that a liquid biopsy test one day in the future could be used to help identify those cases. Say definitively or with greater confidence that it’s one or the other and hopefully prevent the need for a neurosurgical procedure.
I know that what you’re seeing through this liquid biopsy is done with great optics. But if you were just with the naked eye looking at this is different from this, how would you describe that?
Bettegowda: So really what we’re trying to do is zoom into a much finer detail than what previously has been done. The previous technologies have been looking at the entire cell. What we’re doing is going inside the cell to look at small fragments of DNA. So really microscopic levels, and understanding at the molecular level, are there signs of cancer? Not just at a gross level, looking at a tumor, it’s like we’re zooming in to the heart of what’s abnormal in a cancer cell, which are the changes in the DNA. We think that’s really what’s driving it, starting it, making it to grow and progress. And we really think that’s the core of the biology behind cancer initiation or progression and that’s where we’re trying to target our liquid biopsy approaches.
Are you hoping to be able to determine whether or not it’s entirely genetic or environmentally impacted as well
Bettegowda: So we know that cancer in general is a combination of the risk factors that we inherit from mom or dad, a combination with environmental exposures that one goes throughout life, some of which are under our control, unfortunately many of which are not under our control followed by a mixture of things that are incompletely understood currently that go together to unfortunately cause a cancer cell to develop and start to propagate and grow. So our goal one day is indeed to be able to identify folks who may be at higher risk, implement not necessarily this strategy, but a different strategy that might be used as a screening test. Meaning, before a person gets cancer, be able to have a liquid biopsy test, perhaps in the blood or other fluids to say we think you might be someone who’s at higher risk, perhaps based on family history, environmental history, social history, offer a test, like a blood test to say is there signs of cancer brewing even though we don’t see it yet clinically? That’s really our hope and ambition in the years to come and we think a way to impact even more people than with the current approach we’re taking for brain cancer.
Is this fluid the same that washes the brain at night when we sleep?
Bettegowda: It is 100% the same fluid. The body produces a few hundred milliliters of this fluid every day. So it’s constantly being produced, reabsorbed, produced, reabsorbed. So it’s basically bathing the brain. So if there’s a cancer growing in the brain, we think a high probability that’s going to shed material into this water that’s bathing it, goes from the brain down through the spinal cord at the base of the spine and hence how a lumbar puncture, or two or three mls of this fluid can be sampled, can be informative of what’s happening in the brain itself.
Why is the fluid, it’s intuitive and why is that the messenger, the storyteller of the body and the overall picture of what’s going on? Because it goes everywhere.
Bettegowda: So this is a very important fluid for the central nervous system. So it’s able to tell us what’s happening in the brain and spinal cord. It’s not as good at telling us what’s happening in the liver or lungs because it really is circulating around the brain and spinal cord. So this really gives us a snapshot into what’s happening in the nervous system of the body in a very detailed way, in a way that’s not impacted or contaminated by signals from other organs in the body like the lungs, the heart, the kidney, the liver. This really is a precise way to understand what’s happening in the brain. And as a neurosurgeon, we’re focused on brain cancers both that start in the brain, those that spread to the brain because it’s continually bathing it. We think the CSF, this cerebrospinal fluid is a great medium to understand what’s happening there.
END OF INTERVIEW
This information is intended for additional research purposes only. It is not to be used as a prescription or advice from Ivanhoe Broadcast News, Inc. or any medical professional interviewed. Ivanhoe Broadcast News, Inc. assumes no responsibility for the depth or accuracy of physician statements. Procedures or medicines apply to different people and medical factors; always consult your physician on medical matters.
If you would like more information, please contact:
Amy Mone Christopher Douville
Amone1@jh.edu cdouvil1@jhmi.edu
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