Sandeep Burma, PhD, professor in the Department of Neurosurgery at the UT Health Science Center in San Antonio, Texas, talks about how the treatment for glioblastomas might be the cause of their return.
Interview conducted by Ivanhoe Broadcast News in April 2022.
It seems like glioblastomas are so much more prevalent than they once were. Is that the case or can we just diagnose it better?
BURMA: Instead of being a clinician, I’m a basic researcher studying GBM biology by using mouse models. My understanding is that the increase in cases could be due to better diagnosis. I do not think it is way more prevalent than it was in the past but prior exposure to radiation or an aging population could also be factors contributing to any increase. But these tumors are hard to cure, basically.
What are glioblastomas?
BURMA: So GBMs, or glioblastomas, are brain tumors that arise either from the astrocytic population or the stem cell populations of the brain. The problem with GBMs is that they are very hard to cure. Radiation is one of the therapeutic modalities for GBM that works, but only up to a point. So, the average survival could be as bad as only a year after diagnosis.
Is radiation especially difficult to conduct in the brain?
BURMA: Yes. So, we now have better modes of delivery of radiation so that the radiation can be fine-tuned to the tumor. Yet, especially in the context of the brain, you cannot avoid injury to healthy tissues that surround tumors. This is because these tissues also have to be irradiated in order to get rid of the infiltrating tumor cells. GBMs are highly infiltrative. So, yes, normal tissue toxicity is a problem with radiation, however effective it might be. And the other thing, which is sort of what our research speaks to, is the fact that some of that normal tissue toxicity can spur GBM recurrence.
How much more tissue does radiation usually damage? Is there a certain amount of healthy tissue that always becomes a victim of it?
BURMA: Normally, when the brain tumor is irradiated, a two- to three-centimeter margin of normal brain tissue surrounding the tumor also has to be irradiated just to get into the infiltrating tumor cells, which the surgeon is not able to remove. Recurrences usually arise, therefore, in the margin.
That’s what makes glioblastoma so lethal. So, is it like fingers that go out and make it difficult for surgeons to get to it?
BURMA: One of the reasons why they are lethal is the infiltrative nature. The other reason is the fact that they’re very radiotherapy-resistant and resistant to other therapeutic modalities. So, they’re inherently more resistant to the current therapeutic modalities, radiation, and chemotherapy. And the third part of it speaks to the paradoxical nature of radiation, which we find in our lab. Radiation can also spur GBM recurrence.
Does that reoccurrence usually come back within months of the initial radiation or years?
BURMA: Unfortunately, for great four gliomas, or glioblastomas, the recurrence usually occurs within months of radiotherapy. And the recurrent tumor can be even more resistant to the second line of therapy.
Is the radiation sparking the recurrence?
BURMA: Yes, it can, although I do want to emphasize that radiation is still the one therapeutic modality that works for GBM. But it works only up to a point, and the radiation itself could spur the recurrence. So, if we could understand why and how radiation is spurring recurrence, we could keep radiotherapy as a therapeutic modality. But we could perhaps deal with those aspects of radiation, the radiation- induced damage that spurs recurrence, and thereby delay recurrence.
Is there a way to stop that reoccurrence or delay it?
BURMA: That comes from the research that we are here to discuss. This has to do with the fact that the damage to the healthy brain tissues surrounding GBM triggers a process called senescence – an age-related process that cells in the normal brain undergo after radiotherapy. These so-called senescent cells that are generated by radiation can essentially drive tumor recurrence by spitting out growth factors. And a potentially effective therapeutic modality would be to eliminate those senescent cells, those aged cells, by using a very novel and exciting class of drugs called senolytics. Senolytics essentially kill aged senescent cells without affecting normal cells. And these drugs are also generating a lot of excitement in the aging field, in the neurodegeneration field, because such age-related senescent cells can also promote other kinds of pathologies, including COVID lung fibrosis, for example. We are, of course, thinking about senolytics more from the point of view of cancer therapy.
When you say that about age-related brain cells, it automatically makes you think of something like Alzheimer’s or dementia. Does it also impact that?
BURMA: Exactly. So, cells called astrocytes in the brain that become senescent have been shown to impact age-related disorders like Alzheimer’s, which you just mentioned. A host of neuropathologies can be spurred by age-related senescent astrocytes in the brain. In the context of our research, such senescent cells can also be prematurely generated by genotoxic (or DNA-damaging) radiotherapy. So, when you irradiate astrocytes, they can become prematurely senescent or aged. And such senescent astrocytes can then spit out growth factors and other tumor-promoting factors and thereby drive recurrence.
Do you give this drug before the radiation?
BURMA: So, the idea would be to give the drug after radiation. You would come in with the genotoxic radiotherapy, or other genotoxic therapy, and then come in later with adjuvant senolytic therapy to eliminate the senescent cells that could otherwise promote tumor recurrence. And senolytic therapy could also be beneficial from an additional standpoint because radiation also induces, to some extent, senescence in the tumor cells. This is because the tumor cells are rapidly proliferating. So, after radiotherapy, some of these cells stop dividing and they go to the senescent-cell stage. So, the senolytic therapy can also take out that population of the tumor cells, which can also reduce cancer recurrence.
Has this been tested in animal models yet?
BURMA: So, the work we’ve been discussing has been tested in preclinical mouse models of glioblastoma. And of course, more preclinical work has to be done before this concept can move into clinical trials for GBM. The principle has also been shown to be true for other cancers. We are talking about brain cancers, but the principle of senescent cells driving tumor growth has also been shown for cancers of the breast and the lung, for example.
Has it been used in any other trials?
BURMA: I believe there could be some clinical trials, but not for brain cancers. A lot of the clinical trials involving senolytic drugs are really those that are directed more at age-related pathologies, like neurodegeneration including Alzheimer’s disease. And there are clinical trials at UT Health San Antonio that are ongoing.
Are these age-related cells responsible for glioblastomas in the first place?
BURMA: So, GBMs usually occur in the older population, in the “above 60” population. And while we are talking about astrocytes that were rendered senescent by radiotherapy, such senescent astrocytes also accumulate with age. It’s quite possible, although not proven for brain cancers, that such cells in the aged brain could suddenly promote tumor development, not just recurrence, which is also what we are studying.
So, what’s next for your study?
BURMA: So, the current study shows how senescent cells can promote tumor recurrence. The next study would be much more rigorous preclinical studies using mouse glioma models, which would be designed to see if we come in with adjuvant senolytic therapy and if we can really blunt tumor recurrence. This includes whether we can make the recurrent tumor more susceptible to the next round of therapy, which is also something that we posit would be possible. So, from a clinical standpoint, that’s the next line of work that we are pursuing. But from a basic standpoint, we are very keen on understanding whether it’s only the astrocytic population that’s spurring tumor regrowth or whether there are other populations that undergo senescence. That’s one part of it. The second part of it is also very interesting, which has to do with the fact that when we irradiate a tumor, a certain fraction of cells in the tumor, as I mentioned, also become senescent. And those senescent cells, by spitting out these growth factors, could also drive the proliferation of their counterparts that have not undergone senescence, and thereby drive tumor recurrence. So, those are a lot of things that we are keen on pursuing. Although senescence is supposed to be a permanent stage where the cell no longer divides, it is possible that senescent tumor cells can possibly escape senescence. And this so-called senescence escape can lead to the development of cancer stem cells, which are even more dangerous and tumorigenic (tumor-initiating). So, these are the lines of basic research that we will continue to pursue.
Do you find these age cells in young people who get glioblastomas and have radiation? Do you see that their cells age prematurely?
BURMA: I know from work being done in other institutions, for example, that younger patients who have been treated for brain cancers, by the time they’re adults, have a lot of other additional neurodegenerative syndromes and the risk of secondary cancers. So, a patient treated for a grade two glioma could then come back with a grade four glioma. I am aware of clinical trials in other institutions where they are looking into whether senolytics could ameliorate some of these symptoms in these patients who are prematurely aged by radio chemotherapy. Now, in terms of what we have seen, we have also looked at a limited cohort of de-identified brain tumor samples from patients who had received radiotherapy. And we do find evidence of senescence in the healthy brain cells surrounding the tumor, presumably caused by the prior radiotherapy. But it’s a very limited study that we have started on right now.
Are these aged cells not just in the brain, but everywhere?
BURMA: Certainly, yes, any kind of cell treated with radiation can undergo senescence in principle. That speaks to the paradoxical nature of radiation. It is still one of the most effective therapeutic modalities for many cancers, including the brain. Radiation works better than anything else. But unfortunately, radiation is paradoxical in that it can also cause the side effects of therapy that limit treatment. And it can also spur the development of secondary cancers or tumor recurrence. As I just mentioned, the development of secondary cancers could be because of additional genetic changes in the incipient tumor cell itself or radiation-induced senescence in the tumor microenvironment.
Does radiation spark other cancers, secondary cancers, even not in the brain, but throughout the body?
BURMA: Yes, and that is a possibility. For other cancers, too, radiation-induced genetic changes to precancerous cells or senescence-associated changes to the tumor microenvironment caused by radiation could suddenly promote tumor recurrence or the development of perhaps a higher-grade cancer. That does not mean that we do away with radiation altogether. It’s still very effective in many instances, including brain cancers, where radiation is the most effective therapeutic modality. But if we had a better understanding of how these secondary cancers or recurrences develop, then perhaps we could augment radiotherapy with other strategies to avoid these unwanted, undesirable side effects of radio chemotherapy.
So, can you tell us about the mouse study?
BURMA: The mouse study that led to these findings involved brain tumor mouse models that we routinely used. What we found, very interestingly, is that if we were to irradiate the mouse brain first, wait 30 days, and then implant a very small number of mouse glioma cells into the brain, these cells implanted in pre-irradiated brains grew like gangbusters compared to cells implanted in un-irradiated brains. So, there was something about the radiated brain that was really spurring tumor growth. And not only were these tumors growing faster, but they were also a totally different beast altogether. The tumors are much more vascularized. They were much more invasive; they were much more lethal. So, something about the radiated brain was doing this to the implanted tumor cells. And this is where we figured out, by RNA sequencing analysis and other methods, that astrocytes in the irradiated brains are rendered senescent by the radiation, and that these astrocytes were actually spitting out a host of tumor-promoting growth factors and other factors that were really causing these tumor cells to just take off. We also found that if we irradiated the mouse brains and then treated them with the senolytic drug, we could eliminate the senescent astrocytes in the mouse brains. And if we put in tumor cells, the tumor cells didn’t grow as fast anymore because those senescent astrocytes were no longer present. So, that’s the basic study, which then leads us to the next phase, which is a more preclinical study where we’ll see if adjuvant senolytic therapy after radiotherapy can dampen the tumor recurrence and make any recurrent tumor much more prone to the next round of therapy.
END OF INTERVIEW
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