May 4, 2021Miriam Bergeret, MSc
Dr. Gelareh Zadeh, MD, PhD, FRCS(C), FAANS, is Dan Family Chair and Professor of Neurosurgery, University of Toronto. She is head of the Department of Neurosurgery at Toronto Western Hospital and codirector for the Krembil Brain Institute at University Health Network. Dr. Zadeh is a senior scientist at Princess Margaret Cancer Centre where she runs a translational research program at MacFeeters-Hamilton Neuro-oncology Program and holds the Wilkins Family Brain Tumor Research Chair. Dr. Zadeh has a dedicated neuro-oncology and skull base tumor practice, which includes a number of multidisciplinary specialized programs including a skull base clinic, brain metastases, pituitary clinic, and neurofibromatosis clinics. In parallel, she has an active research laboratory focusing on integrated multi-platform molecular analysis of brain tumors, together with a focus on understanding molecular response to targeted therapies, such as anti-angiogenesis and metabolic inhibitors.
Q: Can you tell me about your lab’s work in neuro-oncology?
A: We have a lab that has three main streams. One focuses on genomics and epigenomics of gliomas and skull base tumors, this primarily includes tumors called meningiomas and schwannomas. The second stream looks at animal models that we can use to interrogate the genomic and epigenomic findings within preclinical models. These are mainly mouse models of brain tumors. And the third stream focuses on neurofibromatosis, a syndrome that results in multiple tumors throughout the peripheral nerve, spine, and brain, and all of the conditions related to neurofibromatosis that are primarily tumor related.
Q: How is treating brain tumors different than treating other types of cancer?
A: One of the key points concerns the intimate invasion of brain tumors into normal structures that control brain and neuronal function, such as our language and expression of who we are, our understanding and comprehension, our ability to read, write, etc. For us as neurosurgeons, one of our main goals is to identify corridors and pathways where we can access the tumor through structures in the brain that leave the least amount of damage to avoid changing the person—who they are, their function, and their capabilities. As a result, we’re often limited from being able to completely resect the tumor, and so finding additional methods to treat the residual tumor and avoid recurrence is an essential component of our neuro-oncology practice.
"We’re moving toward being able to use a blood plasma test that can accurately diagnose brain tumors and identify the molecular subtype and features of the tumor."
Q: What tools has your lab developed to tackle these challenges?
A: Yes, as described in our most recent Nature Medicine publication, we’re moving toward being able to use a blood plasma test that can accurately diagnose brain tumors and identify the molecular subtype and features of the tumor. This plasma assay would transform how we manage brain tumors, because often an operation is required to obtain a tissue biopsy and a diagnosis, so if we can move toward using a blood test to confirm that diagnosis, we could avoid the operation and the need for a biopsy.
Next, I think the plasma blood test could be used in addition to MRI, which we use now to evaluate tumor growth, recurrence, progression, and response to treatment, and add the plasma test as a new method that could tell us whether there’s recurrence and how well a patient is responding to treatment. And that’s the cfMEDIP and DNA methylation test that we do on plasma that allows us to be able to detect the tumor accurately and also diagnose it.
Q: What does the DNA methylation pattern tell you about a tumor?
A: Tumor bulk tissue has a DNA methylation signature that’s unique to each tumor. There was a seminal publication in 2018 in Nature that demonstrates that there are approximately 80 different types of brain tumor. Each one of them has a very specific methylation signature like a fingerprint, and that signature is conserved in all DNA related to that tumor. So, when the tumor sheds content into the plasma, you can look for that tumor’s fingerprint in the plasma and identify the tumor type, because the relationship of the plasma methylation to the tumor methylation is almost one to one, so you can say with accuracy that this is the subtype of tumor that’s present in a particular person.
Q: What drove you to turn your attention to a blood test for brain tumors?
A: It was a good opportunity to collaborate with my senior scientist partner Daniel De Carvalho, who had established this as a technique in other cancer types—pancreatic, breast, lung, and leukemia—and he hadn’t explored it in the brain because there was always concern that the blood brain barrier may prevent tumor cells from being shed into the plasma. But we decided to explore it.
At University Health Network, we collect every tumor removed from patients and store their tissues for research, and along with the tumor, we collect blood, so we can compare normal to tumor. So, we had this invaluable opportunity to converge that huge resource with the technique that De Carvalho developed, which allowed us to make this transformative novel discovery.
"This plasma assay would transform how we manage brain tumors."
It’s a very exciting development—it’s paradigm shifting, it’s transformative for the patients. And once we complete our additional prospective samples and demonstrate the true value of this blood test in a real-world setting, then it could be implemented in clinical practice.
Q: At the moment, the blood test is used to confirm diagnoses. But could it be used to predict patient outcomes?
A: If we move toward prospective studies to show that we can detect recurrence early, it will influence treatment by initiating treatment earlier as opposed to waiting to see MRI results. The other area where you could envision it being used is when we see small lesions on an MRI but are uncertain whether we should operate or continue to monitor the patient. When we add the information from the plasma test to the MRI results, and say that, based on the features that we see with the plasma DNA methylation test, there are no concerning features about this tumor, we’ll continue to monitor that patient; whereas if we do the blood test and the features are more characteristic of an aggressive tumor, we would then argue that perhaps we need to intervene earlier and offer surgery sooner.
Q: What are the next steps to advance this technique?
A: Related to this plasma biomarker, I think the next big advance is for us to demonstrate two things: that this could be used as a test for early detection before the tumor has become a significant mass that requires resection, and second, that we can use it as a test to detect recurrence early on before you can see it on an MRI, because by the time you see it on imaging, it’s too late—the tumor’s already quite active. So, we hope the blood test can replace MRI as a more sensitive test.