Health

Groundbreaking Method “Starves” Highly-Lethal Cancer Tumors of Energy, Eradicating Them

Cancer Cell Biology Illustration

According to the researchers, the results provide an encouraging foundation for developing effective glioblastoma treatments. 

New breakthrough in treating glioblastoma, a currently incurable type of cancer.

Ground-breaking research at Tel Aviv University successfully eradicated glioblastoma, a deadly form of brain cancer. The researchers achieved the result by developing a strategy based on their finding of two crucial mechanisms in the brain that promote tumor growth and survival: one shields cancer cells from the immune system, while the other provides the energy needed for rapid tumor growth. The research discovered that astrocytes, which are brain cells, regulate both methods, and that when they aren’t there, tumor cells die and are eliminated. 

Rita Perelroizen, a Ph.D. student, served as the study’s lead researcher. She collaborated with Professor Eytan Ruppin of the National Institutes of Health (NIH) in the United States and was supervised by Dr. Lior Mayo of the Shmunis School of Biomedicine and Cancer Research and the Sagol School of Neuroscience at Tel Aviv. The study was recently published in the journal Brain and was highlighted with scientific commentary.


A short video explaining the research. Credit: Tel Aviv University

The researchers explain: “Glioblastoma is an extremely aggressive and invasive brain cancer, for which there exists no known effective treatment. The tumor cells are highly resistant to all known therapies, and, sadly, patient life expectancy has not increased significantly in the last 50 years. Our findings provide a promising basis for the development of effective medications for treating glioblastoma and other types of brain tumors.”

Dr. Lior Mayo. Credit: Tel Aviv University

Dr. Mayo: “Here, we tackled the challenge of glioblastoma from a new angle. Instead of focusing on the tumor, we focused on its supportive microenvironment, that is, the tissue that surrounds the tumor cells. Specifically, we studied astrocytes – a major class of brain cells that support normal brain function, discovered about 200 years ago and named for their starlike shape. Over the past decade, research from us and others revealed additional astrocyte functions that either alleviate or aggravate various brain diseases. Under the microscope, we found that activated astrocytes surrounded glioblastoma tumors. Based on this observation, we set out to investigate the role of astrocytes in glioblastoma tumor growth.”

Using an animal model, in which they could eliminate active astrocytes around the tumor, the researchers found that in the presence of astrocytes, the cancer killed all animals with glioblastoma tumors within 4-5 weeks. Applying a unique method to specifically eradicate the astrocytes near the tumor, they observed a dramatic outcome: the cancer disappeared within days, and all treated animals survived. Moreover, even after discontinuing treatment, most animals survived.

Dr. Mayo: “In the absence of astrocytes, the tumor quickly disappeared, and in most cases, there was no relapse – indicating that the astrocytes are essential to tumor progression and survival. Therefore, we investigated the underlying mechanisms: How do astrocytes transform from cells that support normal brain activity into cells that support malignant tumor growth?” To answer these questions, the researchers compared the gene expression of astrocytes isolated from healthy brains and from glioblastoma tumors.

Dr. Lior Mayo with students. Credit: Tel Aviv University

They found two main differences – thereby identifying the changes that astrocytes undergo when exposed to glioblastoma. The first change was in the immune response to glioblastoma.

Dr. Mayo: “The tumor mass includes up to 40% immune cells – mostly macrophages recruited from the blood or from the brain itself. Furthermore, astrocytes can send signals that summon immune cells to places in the brain that need protection. In this study, we found that astrocytes continue to fulfill this role in the presence of glioblastoma tumors. However, once the summoned immune cells reach the tumor, the astrocytes ‘persuade’ them to ‘change sides’ and support the tumor instead of attacking it. Specifically, we found that the astrocytes change the ability of recruited immune cells to attack the tumor both directly and indirectly – thereby protecting the tumor and facilitating its growth.”

The second change through which astrocytes support glioblastoma is by modulating their access to energy – via the production and transfer of cholesterol to the tumor cells.

Dr. Mayo: “The malignant glioblastoma cells divide rapidly, a process that demands a great deal of energy. With access to energy sources in the blood barred by the blood-brain barrier, they must obtain this energy from the cholesterol produced in the brain itself – namely in the astrocytes’ ‘cholesterol factory’, which usually supplies energy to neurons and other brain cells. We discovered that the astrocytes surrounding the tumor increase the production of cholesterol and supply it to the cancer cells. Therefore, we hypothesized that, because the tumor depends on this cholesterol as its main source of energy, eliminating this supply will starve the tumor.”

Next, the researchers engineered the astrocytes near the tumor to stop expressing a specific protein that transports cholesterol (ABCA1), thereby preventing them from releasing cholesterol into the tumor. Once again, the results were dramatic: with no access to the cholesterol produced by astrocytes, the tumor essentially ‘starved’ to death in just a few days. These remarkable results were obtained in both animal models and glioblastoma samples taken from human patients and are consistent with the researchers’ starvation hypothesis.

Dr. Mayo notes: “This work sheds new light on the role of the blood-brain barrier in treating brain diseases. The normal purpose of this barrier is to protect the brain by preventing the passage of substances from the blood to the brain. But in the event of a brain disease, this barrier makes it challenging to deliver medications to the brain and is considered an obstacle to treatment. Our findings suggest that, at least in the specific case of glioblastoma, the blood-brain barrier may be beneficial to future treatments, as it generates a unique vulnerability – the tumor’s dependence on brain-produced cholesterol. We think this weakness can translate into a unique therapeutic opportunity.”

The project also examined databases from hundreds of human glioblastoma patients and correlated them with the results described above.

The researchers explain: “For each patient, we examined the expression levels of genes that either neutralize the immune response or provide the tumor with a cholesterol-based energy supply. We found that patients with low expression of these identified genes lived longer, thus supporting the concept that the genes and processes identified are important to the survival of glioblastoma patients.”

Dr. Mayo concludes: “Currently, tools to eliminate the astrocytes surrounding the tumor are available in animal models, but not in humans. The challenge now is to develop drugs that target the specific processes in the astrocytes that promote tumor growth. Alternately, existing drugs may be repurposed to inhibit mechanisms identified in this study. We think that the conceptual breakthroughs provided by this study will accelerate success in the fight against glioblastoma. We hope that our findings will serve as a basis for the development of effective treatments for this deadly brain cancer and other types of brain tumors.”

References:

“Astrocyte immunometabolic regulation of the tumour microenvironment drives glioblastoma pathogenicity” by Rita Perelroizen, Bar Philosof, Noga Budick-Harmelin, Tom Chernobylsky, Ariel Ron, Rotem Katzir, Dor Shimon, Adi Tessler, Orit Adir, Anat Gaoni-Yogev, Tom Meyer, Avivit Krivitsky, Nuphar Shidlovsky, Asaf Madi, Eytan Ruppin and Lior Mayo, 28 July 2022, Brain.
DOI: 10.1093/brain/awac222

“Forced but effective partners in crime: how astrocytes drive the progression of glioblastoma” by Kai Murk and Robert Hülse, 18 August 2022, Brain.
DOI: 10.1093/brain/awac302

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  • There must be many thousands of human patients quite ready to be the 'guinea pigs' they will need, so go at it - high time to get this awful disease at ;ast !

  • 1. When will this be covered by insurances?
    2. Will this only be available for patients that have gone through standard treatments?
    Insurance and regular cancer treatments are BIG money.
    Or will they patent this for so many years and charge big money in order to first recoup their costs before lowering their price?

    My family unfortunately experience d this 1st hand very tragically

  • Why couldn’t this have been figured out a year ago. Yeah famous people died because of it but so did my damn mother. The medical community has done nothing but let me down and now you find something that could have helped. Like good for you guys but also what a slap in the face.

  • I lost my son to a brain stem glioblastoma. Given the choice between a death sentence and a possibility I know what we would have chosen.

  • Fascinating! I had surgery for a tumor of adolescent oligodendroglioma/astrocytoma mix 32 years ago. This type is low grade, fortunately. I love seeing work advance like this.

  • In mice, ALPHA TAU MEDICAL DaRTs wires with radium 224 at tips, by unleashing a cascade of Alpha particles permanently cut all tumor DNA thereby immediately killing all glioblastoma cancer cells.

  • Yes if only this would've been discovered sooner! I pray for those who have lost a love one. My son was diagnosed a year ago. He has three young boys, 13, 3 and 1 yr old. He wants to raise and guide his sons to manhood as would any father. His 13 yr old is having to be part caregiver and help take care of his little brothers while having to attend school virtually. It's taken a toll on his 13 yr old son mentally. My son says, "mom I'm trying for my boys but it's so hard". PLEASE HELP MY SON.

  • Please reach out to UAB and help my sister! Her name is Judy Bledsoe.
    University of Alabama Birmingham

  • Great news, but the authors didn't explain what happens when that is removed? How does it affect the patient or in these cases the animals?
    If cholesterol is essential to us, then removing it also must have dreadful consequences...
    No one wants to be a vegetable.

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