Episode 70: United Against Brain Cancer
Karie Dozer [00:00:03] I’m Karie Dozer and this is TGen Talks. Glioblastoma: It’s the most lethal of all brain cancers. And though treatment can lessen symptoms and slow its growth, there is no cure. Treatment for glioblastoma multiforme or GBM is typically limited to surgical removal of a tumor and radiotherapy or chemotherapy. In fact, there have been no new drug therapies to treat the cancer in the past 25 years. But a new fellowship at TGen is aiming to change that fact. Funded by the families of two patients whose lives were cut short by GBM, this two-year effort hopes to identify new drug therapies and better measure the success of drugs already being used. Here, to talk about her work toward better understanding glioblastoma and furthering research toward better and earlier diagnosis and treatments is Doctor Valerie De Luca. Thanks for taking the time to say hi today.
Dr. De Luca [00:01:00] Yeah. Thank you.
Karie Dozer [00:01:01] Before we talk about your work and your plans for the next two years, tell me a little bit about your work up to today and what caused you to focus your research at this time on glioblastoma.
Dr. De Luca [00:01:11] Sure. So I actually did my undergrad research here at TGen, and I did it under the direction of Doctors William Hendricks and Jeffrey Trent in melanoma. And at that point, I was just trying to get my foot in the door of research. So I fell in love with pharmacology during my undergrad studies here. And that prompted me to go to Virginia Commonwealth University, where I studied under David Gorges lab, doing therapy induced senescence and autophagy in lung cancer, breast cancer and prostate cancer. And so those are functional states or cell processes that are induced by the therapies. So when we’re treating cells, we’re not actually killing all of the tumor cells. And so I’m interested in what are we doing instead of killing them. How are the tumor cells responding. And so that interest is actually what brought me to Doctor Berens’ lab with the brain tumor unit. And so I hadn’t done anything in glioblastoma prior, but he had been looking kind of for a cell biologist that was interested in exactly what I’m interested in. And so obviously, Doctor Berens reputation, what an opportunity to come have some into a new field, into, a really an intersection of spaces that I thought would be great for a postdoctoral position.
Karie Dozer [00:02:30] So how long have you been working on glioblastoma? It sounds like a lot of your work prior translated pretty well.
Dr. De Luca [00:02:36] I would say two and a half years now. So I do think that it has translated well. There’s some commonalities in terms of the pharmaceuticals that we’re using and the way we study it. But glioblastoma really is a beast of its own. So there’s been a little bit of a learning curve as well. I find that with every tumor type, you have to learn its idiosyncrasies.
Karie Dozer [00:02:58] I think most people know that glioblastoma is a beast like you put it. But why? Simply put, why is it so difficult to diagnose and to treat?
Dr. De Luca [00:03:05] It’s difficult for two main reasons, I would say. Of course there’s more, but the two prominent ones are. First, it’s location. So it exists in the brain obviously, which means it’s behind the blood brain barrier. And that is a great hindrance to getting therapeutics to the tumor itself. It also limits our understanding of what’s happening to the tumor. So for more accessible tumors like breast cancer, we can take repeated biopsies from patients. And that means we can look at what’s actually happening to the tumor over time with brain. It’s not that simple. And then the other challenge there is that glioblastoma is exceptionally heterogeneous. And it’s very it’s very different, not just between patients but also within a patient. There’s different subpopulations that make up the tumor itself. And so even if you can successfully treat some cells within the tumor, there’s going to be others that aren’t responding the same way.
Karie Dozer [00:04:04] Do you think that with access to more research, those mysteries and that vast number of subtypes might become more manageable over time?
Dr. De Luca [00:04:14] I think so, I think manageable might actually be the best word for it. I don’t necessarily think that we’ll come across a single therapy that’s capable of eliminating every single sub clone that there is that makes up a GBM tumor, but I think that we are learning and leaning towards combination therapies, and that I think will be not a silver bullet still, but something that gets us closer to a maintenance therapy, if not curative.
Karie Dozer [00:04:44] You’re beginning a two-year fellowship, have just begun a two year fellowship in a in a pretty specific area of glioblastoma research. Tell me what the fellowship is and how it’s defined.
Dr. De Luca [00:04:54] Sure. So the fellowship is the Laurie Lane Andy Spyrow Fellowship. It was created by two families, essentially that had personal losses to GBM. And so that’s really unique in terms of fellowships that we have here at TGen. And very often fellowships come from funding agencies like the NIH or DoD, etc.. And of course, those also come from personal stories, donations to those philanthropic agencies like the American Cancer Society. But having a named fellowship where we can interact with these families, that’s somewhat unique.
Karie Dozer [00:05:29] What are the specific goals of this fellowship?
Dr. De Luca [00:05:31] Yeah. So the specific goals in terms of the science is to bring something hopefully translational. And so that’s a big, lofty goal. It takes a long time to get things from bench to bedside, a lot longer than we would hope. But the goal is to do research that we can at least see having an impact. And so the work that I do, I think is right on that edge. And so the goal is to be able to show the families, show the scientific community that what we’re working on is something that can actually impact patient lives.
Karie Dozer [00:06:05] Tell me a little bit about the scope of the fellowship. What are you actually looking for?
Dr. De Luca [00:06:09] Sure. So it is kind of a two branch, objective. The first is to identify new therapeutic targets, and the other is to bring an accessible assay to patients that let us understand whether drugs are reaching their tumor better. So I had mentioned prior that the blood brain barrier prevents drugs from getting there. It’s also very difficult to understand how much drug is getting there. And so understanding that and understanding that early, especially on a patient-by-patient basis, really could be revolutionary in terms of how we treat our patients.
Karie Dozer [00:06:46] So the very thing that is supposed to protect us by keeping our brain somewhat insulated from outside diseases and toxins, is what makes it so hard to treat this very aggressive cancer.
Dr. De Luca [00:06:57] Yeah, absolutely. I mean, in a physiological sense, the blood brain barrier is fantastic. It is exactly what you said. It keeps us protected from toxins from, you know, viruses, parasites. But in a pathological state like GBM where we’re trying to get a small molecule there, the brain’s just trying to do what it normally does, which is protect itself. And unfortunately, GBM can to some degree take advantage of that.
Karie Dozer [00:07:22] Let’s talk about the area of pharmaceuticals. You’re looking for ideally better drugs to treat glioblastoma. And there have not been a lot of breakthroughs in that area in quite a long time. Will you be testing specific drugs that are in the research process now, or will you be coming up with new ideas?
Dr. De Luca [00:07:39] Yeah, so a little bit of both, I think. So to explain that a little bit, as I mentioned, my graduate research was on therapy induced senescence and autophagy. These things that we call functional states. And so what those are they’re cellular processes that are induced when we treat cells with our drugs. So again, instead of entering a process or some form of cell death, they enter these other survival mechanisms. And the one I’m focused on here is therapy induced senescence. It’s a very unique form of growth arrest. So essentially the tumor cells, instead of dying off when they get hit with therapy, enter this growth arrested state where they’re still doing a bunch of stuff. They’re communicating with each other. They’re communicating with the host’s brain, they’re communicating with the immune system. And we know that the survival of these cells is detrimental. So there’s been a push to eliminate these senescent cells called, Seno Therapeutics, specifically seen a little X. And all that means is it’s a drug that particularly targets senescent cells. And so this is a newer area of research in GBM that are therapeutics and radiation and temozolomide are inducing senescence in GBM is a relatively newer idea that’s coming into the literature. And so pushing into that, you know, therapy and identifying the appropriate drugs that we can treat GBM patients with following traditional therapies. That’s a little bit of relying on drugs that have been identified before, as you know, therapeutics, as well as bringing them into this new space.
Karie Dozer [00:09:18] At the consumer level. We don’t hear about a new drug generally until it reaches the marketplace, whereas you probably hear about all kinds of drugs that will never reach the marketplace. How does a lab like yours go about developing something entirely new?
Dr. De Luca [00:09:32] That’s a good question. It’s definitely a multidisciplinary approach. If you’re talking about developing a new molecule. And usually that involves the cell biologist identifying what you want to target. That involves medicinal chemists coming up with compounds, tweaking those compounds to get them delivered to make sure that they’re being absorbed properly. It’s a really multidisciplinary effort. So a lot of times what we also do is instead of making compounds from scratch. We repurpose compounds. And so that can be done through screens of compounds that are already FDA approved, which are a little bit easier to move forward sometimes. It can also be using tool compounds, which are compounds we know won’t necessarily reach the clinic, but that we know will help us understand. You know, if we had a compound that did the same thing, would that be beneficial?
Karie Dozer [00:10:26] You mentioned a two-pronged approach to your fellowship work. What about the second half better assessment of how current pharmaceuticals or current treatments might be working?
Dr. De Luca [00:10:35] Sure. So the problem there is their access to the tumor and knowing on a patient-by-patient basis how much is getting to their tumor. So we’ve talked about the blood brain barrier in GBM. The blood brain barrier can be deteriorated at least in some parts of the tumor. And for some patients they may have more deterioration than other patients. And so the extent to which drugs are crossing the blood brain barrier and permeating the tumor can be different on a case-by-case basis. So understanding how much tumor is getting exposed to drug or whether even if it’s a binary, yes, the tumor is being exposed. No, the tumor is not would be helpful very early on for early phase clinical trials, where we’re trying to decide whether a drug will be efficacious in any patients and on clinically approved drugs, when we’re trying to figure out if a patient is going to respond. And so the goal of this project is to develop a accessible assay and accessible assay where patients can get something simple like a blood draw. And we can use analytes or small molecules within the blood draw to tell us whether or not the drug is interacting with the tumor.
Karie Dozer [00:11:50] It sounds like it’s a twofold problem. You not only need to figure out whether that drug is actually accessing the tumor, but then once it reaches the tumor, whether or not it’s effective.
Dr. De Luca [00:12:01] That is the challenge. And unfortunately, it’s compounded on itself exactly like you said, it’s even if we do get the drugs there, it doesn’t seem like our drugs are doing the job. They’re promoting all of these other survival mechanisms rather than killing the cells. And so this is exactly what makes not just GBM, but cancer in general really difficult to treat. But I think understanding and knowing why we’re doing the work and having some type of motivation beyond just getting an experiment to work on any given day, helps you know that motivation to move forward. I don’t really interact with patients often. So having the Laurie Lane and Spyro fellowship and meeting the families and seeing people affected, that helps reground the purpose and why we put up with our experiments failing every now and then. Right? So there’s the everyday failures, and then there’s the bigger picture that we’re constantly trying to move towards.
Karie Dozer [00:13:01] Does the fact that glioblastoma has been such a difficult area of research in the past make it a little bit easier to conduct the research in that people are more willing to participate, because so far, there just aren’t so many answers.
Dr. De Luca [00:13:15] I don’t know if patients are more or less willing, but I will say that we’re talking with clinicians that we collaborate with. They always speak very highly of their patients and their patients generosity. And knowing that the research that we’re doing, unfortunately, won’t necessarily affect them. Patients are very altruistic and in wanting to help future patients. And so I would say, I don’t know if that’s different across cancer types, but it’s surely prevalent in GBM patients.
Karie Dozer [00:13:45] Is there anything that I that I missed? Is there anything that I haven’t asked about your research that you’d like to talk about?
Dr. De Luca [00:13:50] Yeah, I think I’d like to talk about exactly how we’re approaching these questions, and how are we actually going to develop these assays that can enhance patient care. And, and for us, where we’re approaching it from these particles called extracellular vesicles, they’re membrane bound particles that are secreted from tumor cells. They’re secreted from really every cell in the body, but at a much higher rate by GBM cells. And they’re distributed it to some degree into the CSF, into the plasma, into urine. And so this gives us a really accessible way to get a readout of the tumor. And so what we’re hoping is that by using these bio fluids like plasma, which again comes from a very simple blood draw, that we can isolate these particles and get a little snapshot of what’s going on from the tumor, because again, they come from the tumor. So to some degree they reflect what was happening in it.
Karie Dozer [00:14:47] Doctor DeLuca, thanks for your time today. Thanks for sharing your plans for the fellowship and your plans for the next couple of years.
Dr. De Luca [00:14:53] Yeah. Of course. Thanks for having me.
Karie Dozer [00:14:56] For more on TGen’s research, go to TGen dot org slash news. The Translational Genomics Research Institute, part of city of Hope, is an Arizona based nonprofit medical research institution dedicated to conducting groundbreaking research with life changing results. You can find more of these podcasts at TGen dot org forward slash TGen Talks, Apple and Spotify and most podcast platforms. For TGen Talks, I’m Karie Dozer.