Glioblastoma Spreading Strategies Discovered

Ute Eppinger

October 24, 2022

Every year, around 7000 people in Germany develop a brain tumor, and around half of those cases involve a glioblastoma, a particularly aggressive form of the disease. Glioblastomas are incurable, but advances are being made in both diagnostics and therapy. Scientists from the Heidelberg University Hospital (UKHD) and from the German Cancer Research Center (DKFZ) in Heidelberg have discovered a fundamentally new way in which glioblastomas spread within the brain.

Medscape spoke to Wolfgang Wick, MD, medical director of the neurologic clinic at UKHD, about how glioblastomas are treated; the role that vaccinations, recombinant proteins, and parvoviruses play; and what therapeutic approaches might be derived from the discovery of this method by which glioblastomas spreadi.

Medscape: Glioblastomas spread through the brain like a fungal network. So how would a glioblastoma currently be treated? The tumor can only be partially removed through surgery.

Wick: Nevertheless, glioblastoma would be operated on. This would have a significant effect. Relieving the strain of the main tumor mass, without generating a new deficit, is prognostically very good for the patient concerned. However, surgery on glioblastoma is never curative.

The reason a cure is not possible is down to the special form and spread of the glioblastoma. Nevertheless, an operation helps. This seems to be because removing the main tumor mass maybe has a positive immunological effect. But it may also be connected to the tumor's network communication. The surgical intervention stimulates the network by increasing resistance.

If the main tumor mass is decreased through a surgical procedure, this results in an at least temporarily improved starting position for the patient until the mass regenerates. This could also be connected to the fact that tumor communication is not unregulated but is rather in accordance with a certain hierarchy and order, which requires a certain structure and mass.

The other aspect is that support can be requested via this communication. You can imagine that a cell connected to another cell via a conduit receives help from this other cell in the form of organelles by exchanging ions and that, for example, stress or toxicity can be much better balanced out in large networks than in small networks. That means that external attacks, such as a surgical intervention, can be much better balanced by a well-organized network than by isolated cells.

Resistance to Chemotherapy

Medscape: How do irradiation and chemotherapy rank in the treatment of glioblastomas?

Wick: Irradiation is another therapeutic approach. It causes cells to be stuck in the growth phase of the cell cycle. The cells are not killed through radiation, but they are practically halted. And this arrest of the cell cycle is often sufficient to help people with glioblastomas for a very long time. But the same is true for irradiation as for surgery. This deep network of cells cannot be addressed.

Attempts have been made in the past to reduce the radiation dose to the extent that the brain is no longer damaged by it, but this low dose was then not sufficient to exert any control. If you want to control the tumor, the dose must be high and the volume must be correspondingly low, since there is a clear limit.

Every patient is offered alkylating chemotherapy. At the moment, just one substance is used here in the primary therapy: temozolomide. The problem with this is that two thirds of tumors in all cells exhibit a resistance to this alkylating chemotherapy, which means that the efficacy of this therapy is highly limited in two thirds of patients.

In the one third of patients in whom this resistance is not present, the chemotherapy works fairly well. But even then, it is unfortunately only a matter of time until there is a relapse or disease progression. In my practice, this has always been the case, but there are people who have been living with this disease for 20 years now. There seem to be tumor cells that calmly and silently survive this phase of chemotherapy and then restart the cell cycle at some point.

Medscape: What do you think of alternating electric fields as a therapy option?

Wick: Therapy with alternating electric fields is currently being used and offered to patients. This means that patients who have survived well through radiochemotherapy should also be offered treatment with alternating electric fields.

However, what happens in this process is not as well understood as with other therapies. It is assumed that the cell cycle, ie, cell division, is altered by disrupting the mitotic spindle. But you can imagine, and this is now speculation, but quite sound speculation I believe, that alternating electric fields also cause a certain amount of confusion in the previously described networks. But this still needs to be investigated in more detail.

It is not implausible. We know that such alternating electric fields disturb the organization of cell organelles. And we also know that for this communication, we need fairly good order and also organization. This would definitely be a starting point on the way to understanding why this therapy potentially shows a certain effect in some patients.

Nerve Cell Precursors

Medscape: Scientists from the UKHD and the DKFZ have discovered a new glioblastoma spreading strategy and have learned that the tumor cells imitate the properties and movement patterns of nerve cells. They are labeling the results a "milestone in the field of cancer neuroscience." Could you explain a bit more?

Wick: Glioblastoma does not grow on its own as a solid mass, but instead, the entire brain is affected by the disease. The question of how the tumor's individual cells move the main tumor mass from afar, how they get there, how they continue to be supplied, and what their interaction partners are — an entirely new light has been shed on all of this in our work.

The development of tumor cell mobility has been recognized as a remnant of brain development. The tumor cells have retained properties that the precursor cells for nervous-system development require for an organized nervous system to emerge from just a few cells. This means that the tumor cells copy or eventually retain properties of the nerve-cell precursors that, unlike mature nerve cells, are mobile to a fairly high degree.

Mobility here means that it can advance along a network, despite said network being very densely packed. This also means that certain processes, such as releasing and then continuing to move again, must function and that the communication regarding the original disease must be maintained.

First, we understand what the different glioblastoma cell types do, which molecular properties are associated with which behaviors, and which cell type (namely the swarming cells) is responsible for the invasive tumor growth. In contrast, the network-forming cell type, which only develops from these, is responsible for the resistance.

Interrupting Communication

Medscape: Which starting points for new therapies do you see?

Wick: In terms of new therapies, these movement phenomena are one good starting point. The other starting point — I find this one much more interesting — is that the programming steps that these tumor cells use is no longer needed. This is because our mature nervous system no longer requires this program, which was necessary for the mobility of cells in development.

Our central nervous system exhibits little cell movement. This is to do with programs of nervous-system development that are switched off in the mature nervous system. But they are then reactivated or remain active in the tumor cells. This process reveals potential starting points for therapy.

Addressing the movement of cells, that has been investigated for the last 20 years, but it seems to have an extraordinarily high number of side effects, because these movement mechanisms are also important for other, healthy cells in the body. For example, digestive mechanisms and other proliferation mechanisms, on mucous membranes, in the blood system, in the bone marrow, are then affected and no longer function.

There is another possible approach: the more-or-less specific interaction between the nerve cells and the tumor cells also offers starting points for therapies, from our point of view. The key word is epilepsy treatment. We know that people with brain tumors suffer badly, or worse than usual, from epileptic seizures. This was often regarded purely as a pressure problem. There is a disruptive element in the brain, and this causes the electrical activity in the brain to become disorganized. For some people, this can lead to seizures in certain situations.

The communication between tumor cells and nerve cells takes place via transmission substances, eg, through the neurotransmitter glutamate. Now you can consider whether a "surplus" of communication, such as an excessively strong stimulus, can trigger epileptic seizures.

In this work, we demonstrate that by interrupting this communication, we can also prevent the movement of these cells and the growth, the proliferation, of these cells.

Medscape: What is the significance of parvoviruses for therapy?

Wick: The major topic for cancer is immunotherapy. And one option for performing immunotherapies lies with viruses. Parvoviruses are a plausible therapy for proliferating cells.

Parvoviruses are usually administered locally. This means that a surgical cavity is infected with the viruses and the tumor cells that remain after an operation will then hopefully be killed off by these viruses.

This is the first step and the immediate effect of virus therapy. The attempt is made to kill off cells in the same way as with a medication. The advantage of viruses is the high specificity, ie, only dividing cells will be attacked. In addition, parvoviruses are so small that they can also spread well and circulate through the brain.

The second reason for immunotherapy is that when killing off cells with viruses, antigens are often released that otherwise would not be, depending on the virus. But it's the case with parvoviruses. They integrate with the virus's genetic material. When cells rupture, certain proteins are then revealed, hybrids of viruses and the human genome, and these are attractive to the immune system.

There is a whole range of studies on this subject. However, there are currently no randomized studies that directly compare the therapies. But the expectation is that the use of parvoviruses could be a good addition to therapy.

One limitation that should be mentioned is that the use of viruses may be beneficial for some patients, but it will not have an effect in every patient. What is exciting about parvoviruses is that these viruses can be injected via the bloodstream and still achieve a good effect in the brain.

Protein APG101

Medscape: How relevant is the recombinant protein APG101 to therapy?

Wick: APG101 is a protein that simulates the cell-death receptor CD95 and binds with a stable antibody fragment. By doing so, it blocks the signaling pathway between CD95 ligand and receptor. The interaction between the CD95 ligand and the CD95 receptor activates an intracellular signaling pathway, which in turn stimulates the invasive growth and migration of tumor cells.

APG101 blocks the CD95 ligand and thereby prevents the activation of the CD95 signaling pathway, which leads to a reduction in the invasive cell growth and migration.

Apoptosis, programmed cell death, is a system we have used throughout our evolution to kill off the cell components we no longer need. During tumor development, this system is perverted, so to speak. Here, the stimulation of this system does not actually lead to cell death but rather to cell movement (ie, to cell mobility). And in principle, APG101 blocks this mobility.

To date, I only know of three studies in which the medication has been used for tumors. One study was published 8 years ago. We demonstrated that we can achieve a relatively good effect with APG101 in connection with repeat irradiation, compared with repeat irradiation alone. We consider this effect to most likely be due to this influence on cell mobility.

There is a study on primary therapy: a four-arm study by the Neuro-Oncological Working Group (NOA). The results are still not available, however. In addition, a study on primary therapy with APG101 is currently being conducted in China. It is investigating whether the mechanism of action influences mobility. Whether it will be pushed through as therapy remains to be seen.

Vaccinations and Antigens

Medscape: Vaccinations are of course a part of immunotherapy. What is their status?

Wick: We are looking at the IDH1 protein, which is present in mutated form in a group of brain tumors, as a very good target for a vaccine. The reason is that the protein is present in its mutated form in every cell of the tumor but not in healthy cells. That is a prerequisite for immunotherapy.

We started a study with peptides a few years ago. These peptides are injected under the skin on the stomach and leg. They cause an immune response systemically and in the brain tumor. This immune response may cause an inflammatory reaction (we can demonstrate this inflammatory reaction). And in this noncontrolled study, the approach was successful, at least compared to historical controls. There is no randomized study with treatment-naive control patients.

However, we are cautious because we know that peptide, unlike CAR-T cells or RNA-based vaccines, for example, only triggers a relatively small immune response in many patients. The scale of the immune response is important, rather than the specificity. The scale is probably not large enough in most patients for a long-term effect to be expected.

But there are exceptions. Patients we vaccinated many years ago still have a very remarkable immune status. But we also have patients in whom an immune status cannot even be seen anymore, after just a short period of time.

Therefore, our aim is to perform the immune strategy with more effective, stronger measures — not more specific, but stronger. Unfortunately, it is often the case with glioblastomas that there is not a single antigen that can be vaccinated against. Instead, a relatively large cocktail is needed, which unfortunately also often varies from patient to patient. The conditions are difficult.

Medscape: You mentioned that glioblastomas can be classified into subgroups. Does this improve the prognosis?

Wick: Yes, in certain subgroups the prognosis improves. That is the case with those usually very small groups that are molecularly well defined. I believe that by better understanding the individual groups, we have succeeded in making major progress in those groups. But where there is light, there is also shadow. We know that there are many groups with which we have not achieved a great deal.

Fundamental research leads to a better understanding, and the next step in this is to be able to adapt the therapy. Instead of it being one therapy for everyone, it will become a part of various differing therapies for these quite different groups. We are making a lot of progress with individual groups. But unfortunately, we have not come quite as far as we want with many patients.

Medscape: Thank you very much for the conversation.

This article was translated from the Medscape German edition.

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