With just a 10% three-year survival rate and 90% recurrence rate, glioblastomas are among the deadliest tumors. Most prevalent in adults, the tumor increases in frequency with age and gender, striking men more than women . I recently spoke with Dr. Linda M. Liau, MD, PhD, MBA, a professor, director of the brain tumor program, and chair of the neurosurgical department at the University of California, Los Angeles about her work concerning glioblastomas. She currently works in the field of advances in glioblastoma treatments, and took the time to answer questions regarding the approaches of modern treatments and what the future holds.
MB: Hi Dr. Liau. I’d like to thank you for taking the time to let me interview you. I’m going to start with a couple of intro questions. Have you always wanted to go into the neurosurgical field?
Dr. Liau: I decided to go into neurosurgery probably my third year of medical school.
MB: You started a lab when you first came to UCLA. What were the research questions you explored when you first began?
Dr. Liau: I have always been very interested in Neuroscience, and that’s kind of what I did research on in medical school, and wanted to learn more about the function of the brain and brain recovery. That’s what led me to go into neurosurgery. During my residency, my mom passed away from cancer that had metastasized to the brain, so that’s kind of how I got interested in cancer, and I think a good convergence of those two interests led me to explore research questions relevant to neurological cancer. And I started my lab with the fundamental question of how do you treat and cure glioblastoma.
MB: The current standard of treatments for glioblastomas temporarily work, but after 4-6 months the tumor can recur. What would you say is the primary cause of that?
Dr. Liau: I would say that the main cause of the recurrence of glioblastomas is the fact that these tumors are very heterogeneous. Given that it’s not just one cell type, it’s actually a multitude of cell types. So even if you have a treatment that affects, let’s say, a third of the cells, and get a response, the remaining cells that aren’t responding then outgrow and come back, so that’s a problem. It’s not going to be ‘one treatment fits all’, in the sense that because of the heterogeneity of the tumor, not one treatment is going to kill every single cell within a heterogeneous mass. So, I think what we call the “durability of response” is very low. I mean, you have a response but it’s not durable.
MB: So, treatments that do work would work for 4-6 months, and then following the tumor recurrence, would the same treatment work again?
Dr. Liau: It depends. The problem with these tumors is that not only it is heterogeneous within one patient…it’s also heterogeneous over time. So, once you treat that tumor, 4 to 6 months from now, it may be different.
MB: Dr. Bachoo of the Simmons Cancer Center spoke about how new genetic mutations are no longer required for continued tumor growth. What would be the primary reason behind this being the case?
Dr. Liau: So, for instance, for a tumor like a glioblastoma, there’s not just one mutation, or two or three. There’s probably hundreds. If you think about it, there are already a multitude of genetic mutations. And, as those propagate they may continue to mutate, or even in response to treatment they may change in terms of their mutational profile. In general, they may outgrow whatever treatment you are giving to them at that time.
MB: Have you used magnetic resonance imaging (MRI) and metabolic data in advanced treatment plans?
Dr. Liau: Yes, we actually use MRI scans pretty much for all our patients both for planning, for instance surgical resection, but also for determining whether a tumor has recurred or is responding to treatment. So, an MRI is pretty standard. In terms of metabolic data, we do PET (positron emission tomography) scanning. And UCLA is actually a big PET center. We have several cyclotrons here so we have a lot of research protocols that use different types of PET tracers to look for different aspects of tumor metabolism.
MB: You just talked about surgical resection. Would you say that has been among the more successful methods of complete tumor resection in the past?
Dr. Liau: I would say that surgical reception is useful to obtain a tissue diagnosis. In order to obtain a pathological and now a molecular diagnosis. And because of the heterogeneity of the tumor just doing a tiny little needle biopsy I don’t think is reflective of the true pathology of the tumor usually because you may miss another cell type within there. So that’s one advantage and then the second advantage of surgery is a phenomenon that we call cytoreduction. So if you have a big tumor if you are able to reduce that surgically to the extent to which, for example, if you have trillions and trillions of cells and you are able to reduce it to thousands of cells even though you can’t get every cell, there’s just fewer bulk of tumor that radiation or chemo or any of these other treatments need to work on to get to the cancer.
MB: So, it’s been somewhat successful in the past?
Dr. Liau: Generally, it does offer some therapeutic benefit but it’s not certainly not the cure for these tumors.
MB: Makes sense given the complexity of the tumor. Can you talk about how signaling pathways can be activated constitutively in migrating glioma cells?
Dr. Liau: So, a lot of times these signal pathways usually are activated when you have a receptor and you have something that triggers the receptor and then that’s how that pathway goes on. But when they talk about the constituent activation they don’t have the receptor anymore, but they, that process keeps going on due to some mutation in the cell, so even though you have a drug that affects the receptor…once the cells mutate to the point where they are no longer responsive to the receptor and they’re just, you know, operating on their own, then that drug no longer has an effect.
MB: Got it. So, in general, signaling pathways have worked for other tumors in general but glioblastomas with the level of heterogeneity and complexity?
Dr. Liau: Yeah. And again, the responses aren’t very long and they’re not very durable.
MB: Looking at novel drugs like temozolomide , are they becoming more and more prevalent in revolutionary treatments?
Dr. Liau: Temozolomide is actually now standard of care for glioblastoma. Unfortunately, beyond radiation and temozolomide there really hasn’t been a whole lot else of that has been approved as standard treatment for these tumors. And you know, alkylating agents have been around for decades. I think Temozolomide has gained approval because it’s well-tolerated in general. It’s an oral pill as opposed to a heavy-duty IV chemo. And it’s readily accessible.
MB: Are you guys consistently using it?
Dr. Liau: Currently, a lot of experimental treatments are given in addition to standard treatments meaning radiation and Temozolomide plus the experimental treatment versus the placebo. It’s not really given in lieu of standard treatment because there’s nothing out there that uniformly is able to affect, for instance, all glioblastomas.
MB: So, molecular cellular therapies as well as local drug delivery being used to complement conventional treatments, in addition to having the original treatment?
Dr. Liau: Yeah exactly, I think that over time there are probably going to be different subgroups of these tumors, some that respond really well to metabolic inhibitors, some that respond to other kinds of signaling pathway inhibitors, some that respond to immune therapies. But it’s not going to be one treatment for all these groups.
MB: Would you say that neurodevelopmental transcription factors  drive the growth of glioblastomas?
Dr. Liau: Some of them, yes.
MB: Would you say are there any solutions to really inhibit them in particular?
Dr. Liau: Good question. Transcription factors are hard targets for treatment. They are kind of targets that are deemed less “druggable” than, for instance, a receptor antagonist or things like that.
MB: So, in that situation what would you guys use to inhibit the transcription factor?
Dr. Liau: Depends on the transcription factor. Depends on what type of transcription factor.
MB: And then the dendritic cell vaccination?
Dr. Liau: So, dendritic cells are an antigen-presenting cell. So, they’re actually a cell that is a normal cell in the body. And the concept is that because, for instance, a brain tumor is in the brain. These cells actually don’t get to the tumor, so the antigen-presenting cell doesn’t really have contact to the antigen to produce an immune response. So, the dendritic cell vaccine that we’ve developed is really taking a patient’s own antigen-presenting cells and put them together with the tumor antigens to activate T-cells, which are the cells that go to attack the tumor. And we’ve tried various combinations of ways to activate the dendritic cells. But so far, still using the patient’s own tumor seems to the most efficacious method, probably because of what I have talked about before, the heterogeneity of the tumor. It’s hard to make a designer vaccine with all these hundreds of mutations that it would work for everybody.
MB: So is there anything that stands out to you about glioblastomas compared to other tumors? You mentioned the heterogeneity as the primary reason.
Dr. Liau: Yes, I think it’s the heterogeneity both in terms of heterogeneity within the patient, the heterogeneity between patients, so if you have a hundred patients with glioblastoma they all have somewhat different cell types and mutations and then also the heterogeneity and the transformation over time so as you treat with one drug then when you go back in and for instance operate on the tumor again that tumor at that point in time actually has changed from the original. So that makes it hard, as you essentially have a moving target in terms of how you are trying to treat.
MB: Oh, I see what you mean. And overall, what would you say is the most revolutionary treatment right now?
Dr. Liau: I don’t think there’s particularly one revolutionary treatment. I think there’s probably, you know, groups of treatments and they’re probably going to work in different subgroups of patients, so I think there’s a concept of, as you talked about, you know, changes in metabolism. So, there’s a thought that for instance if you treat a tumor with an EGA foreign inhibitor, though the inhibitor hasn’t shown a durable effect, it works for a little bit and then a few months later the tumor grows back. What we do see if you treat with the inhibitor for instance…sometimes what that does is it actually changes the metabolism of the cell environment. And then it’s in a more vulnerable state. So, if you go in at that time and hit it with another agent, it’s almost like a one-two punch. And hopefully try to kill the tumor with this kind of combination of a cell signaling inhibitor and a metabolic agent or an apoptotic agent. So that’s I think one category. And another category of treatments are immune-based therapies, things like tumor vaccines, Car-T cells, checkpoint inhibitors. I think each individually may have some efficacy, but I think there’s going to be, in the future probably, you know smarter combinations of kind of immune-based approaches. Probably similar to this, where you need probably two drugs to really melt down the tumor. You may need, for instance, a vaccine to get the T-cells into the tumor but then the T-cells are being suppressed by agents that are immune checkpoint inhibitors that are released by the tumor so you need another agent to block those.
MB: Are you working on new treatments or building off what you have done before?
Dr. Liau: No, we’re working on all these new treatments. We have a huge brain tumor program at UCLA. We have researchers and clinicians working in all these areas, like I said, the metabolic vulnerability, we have immune-based therapies, we have treatments that are targeting cancer stem-like cells. One thought about why tumors come back is because there are these stem cells that are resistant to radiation and actually may be triggered by radiation to become tumors. And we are working on ways to counter those.
MB: So I think that’s it. Thank you for taking the time.
Dr. Liau: Thank you.
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