The innovative method “starves” very deadly cancerous tumors of energy, destroying them

According to the researchers, the results provide an encouraging basis for the development of effective treatments for glioblastoma.

A new breakthrough in the treatment of glioblastoma, a currently incurable type of cancer.

Groundbreaking research on Tel Aviv University successfully eradicated glioblastoma, a deadly form of brain cancer. The researchers achieved the result by developing a strategy based on their discovery of two important mechanisms in the brain that promote tumor growth and survival: one protects cancer cells from the immune system, and the other provides the energy needed for rapid tumor growth. The study found that astrocytes, which are brain cells, regulate both methods, and when they are absent, the tumor cells die and are eliminated.

Rita Peralroisen, Ph.D. student, served as lead researcher on the study. She collaborated with Professor Eitan Rupin National Institutes of Health (NIH) in the United States and was led by Dr. Lior Mayo of the Shmunis School of Biomedicine and Cancer Research and the Sagol School of Neurology in Tel Aviv. The study was recently published in the journal The brain and was distinguished from sciences comment.

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

The researchers explain: “Glioblastoma is an extremely aggressive and invasive brain cancer for which there is no effective treatment. Tumor cells have a high resistance to all known methods of treatment, and unfortunately, the life expectancy of patients has not increased significantly over the past 50 years. Our results provide a promising basis for the development of effective drugs for the treatment of glioblastoma and other types of brain tumors.”

Portrait of Dr. Lior Mayo

Dr. Lior Mayo. Author: Tel Aviv University

Dr. Mayo: “Here we approached the problem of glioblastoma from a new angle. Instead of focusing on the tumor, we focused on its supportive microenvironment, that is, the tissue surrounding the tumor cells. In particular, we studied astrocytes, a major class of brain cells that support normal brain function, discovered about 200 years ago and named for their star-like shape. Over the past decade, research by us and others has revealed additional functions of astrocytes that either alleviate or worsen various brain diseases. Under the microscope, we found that activated astrocytes surround glioblastoma tumors. Based on this observation, we decided 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 to 5 weeks. Using a unique method of specifically destroying astrocytes near the tumor, they observed a dramatic result: the cancer disappeared within days, and all the animals that received the treatment survived. Moreover, even after treatment was stopped, most animals survived.

Dr. Mayo: “In the absence of astrocytes, the tumor disappeared rapidly and in most cases there was no recurrence – indicating that astrocytes are important for tumor progression and survival. So we investigated the underlying mechanisms: how do astrocytes transform from cells that support normal brain activity to cells that support the growth of a malignant tumor?’ To answer these questions, the researchers compared gene expression in astrocytes isolated from healthy brains and from glioblastoma tumors.

Dr. Lior Mayo

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

They found two main differences – thus revealing the changes that astrocytes undergo when exposed to glioblastoma. The first change occurred in the immune response to glioblastoma.

Dr. Mayo: “The tumor mass includes up to 40% of immune cells – mainly macrophages recruited from the blood or from the brain itself. In addition, astrocytes can send signals that call immune cells to areas 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 induced immune cells reach the tumor, the astrocytes “convince” them to “switch sides” and support the tumor instead of attacking it. In particular, we found that astrocytes alter the ability of recruited immune cells to attack the tumor both directly and indirectly – thereby protecting the tumor and facilitating its growth.’

A second change by which astrocytes support glioblastoma is the modulation of their access to energy—through the production and transfer of cholesterol to tumor cells.

Dr. Mayo: “Malignant glioblastoma cells divide rapidly, a process that requires a lot of energy. With access to energy sources in the blood barred by the blood-brain barrier, they must obtain that energy from cholesterol produced in the brain itself, namely in the astrocyte “cholesterol factory” that normally supplies energy to neurons and other brain cells. . We found that the astrocytes surrounding the tumor increased the production of cholesterol and provided it to the cancer cells. Therefore, we hypothesized that since the tumor depends on this cholesterol as its main source of energy, eliminating this supply would starve the tumor.’

The researchers then engineered the astrocytes near the tumor to stop expressing a specific protein that transports cholesterol (ABCA1), thereby preventing them from dumping cholesterol into the tumor. Once again, the results were dramatic: without access to the cholesterol produced by the astrocytes, the tumor essentially “starved to death” in just a few days. These remarkable results were obtained in both animal models and human glioblastoma samples, and are consistent with the researchers’ fasting hypothesis.

Dr. Mayo notes, “This work sheds new light on the role of the blood-brain barrier in the treatment of brain diseases. The normal purpose of this barrier is to protect the brain by preventing substances from the blood from passing into the brain. But in the case of brain disease, this barrier makes it difficult to deliver drugs to the brain and is considered an obstacle to treatment. Our results suggest that, at least in the specific case of glioblastoma, the blood-brain barrier may be useful for future treatment because it creates a unique vulnerability—the tumor’s dependence on brain-produced cholesterol. We believe that this weakness may turn into a unique therapeutic opportunity.”

The project also examined databases of 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 cholesterol-based energy. We found that patients with low expression of these identified genes lived longer, supporting the concept that the identified genes and processes are important for the survival of glioblastoma patients.”

Dr. Mayo concludes, “Currently, the tools to eliminate tumor-surrounding astrocytes are available in animal models, but not in humans. The challenge now is to develop drugs that target specific processes in astrocytes that promote tumor growth. Alternatively, existing drugs could be repurposed to inhibit the mechanisms identified in this study. We believe that the conceptual breakthroughs presented by this study will accelerate progress in the fight against glioblastoma. We hope that our findings will inform the development of effective treatments for this deadly brain cancer and other types of brain tumors.”

List of references:

“Immunometabolic Regulation of the Tumor Microenvironment in Astrocytes Drives Glioblastoma Pathogenicity” Rita Peralroisen, Bar Filosof, Noga Budyk-Harmelin, Tom Chernobylsky, Ariel Ron, Rotem Katsir, Dor Shimon, Adi Tesler, Orit Adir, Anat Gaoni-Yogev, Tom Meyer, Avivit Krivitsky , Nufar Szydlowski, Assaf Madi, Eitan Rupin and Lior Mayo, 28 July 2022. The brain.
DOI: 10.1093/brain/awac222

“Awkward but effective partners in crime: how astrocytes contribute to glioblastoma progression” by Kai Murk and Robert Hulse, 18 Aug 2022. The brain.
DOI: 10.1093/brain/awac302 The innovative method “starves” very deadly cancerous tumors of energy, destroying them

Back to top button