Brain cancer growth can be stopped by removing one protein

The growth of certain aggressive brain tumors can be halted by cutting off their access to a signaling molecule produced by the brain’s nerve cells, according to a new study by researchers.

When the signaling molecule neuroligin-3 was absent, or when its signal was interrupted with medication, human cancers called high-grade gliomas could not spread in the brains of mice, the researchers found. 

“We thought that when we put glioma cells into a mouse brain that was neuroligin-3 deficient, that might decrease tumor growth to some measurable extent. What we found was really startling to us: For several months, these brain tumors simply didn’t grow,” said assistant professor of neurology and senior author of the study. The findings suggest that interrupting the neuroligin-3 signal could be a helpful strategy for controlling high-grade gliomas in human patients, Prof. added.

High-grade gliomas are a group of deadly brain tumors that include adult glioblastoma,  anaplastic oligodendroglioma; pediatric glioblastoma; and a pediatric tumor called diffuse intrinsic pontine glioma. Five-year survival rates are 60 percent for anaplastic oligodendroglioma, around 10 percent for adult and pediatric glioblastomas and virtually nonexistent for DIPG. New treatments are urgently needed.

Hijacking the normal machinery

Earlier, the scientists showed that neuroligin-3 fueled the growth of high-grade gliomas. This was surprising because the protein is a part of the normal machinery of neuroplasticity in a healthy brain, and it is a relatively new concept that cancer can hijack an organ’s healthy function to drive cancer growth.

In the new study, the team examined mice that were genetically engineered to lack neuroligin-3. These mice have nearly normal brain function. However, when their brains were implanted with any of the forms of human high-grade glioma, the cancer cells could not proliferate. The growth stagnation persisted for several months.

“Lack of neuroligin-3 doesn’t kill the cancer cells; the cells that are there remain there, but they do not grow,” Prof. said. However, 4½ months after implantation, tumors in some mice circumvented their dependency on neuroligin-3 and began to grow again, she added.

Effect specific to high-grade gliomas

The researchers also tried implanting the brains of mice lacking neuroligin-3 with human breast cancer cells. Lack of neuroligin-3 did not affect breast cancer growth, showing that the effect is specific to high-grade gliomas.

The growth-stagnation effects, conserved across different classes of high-grade glioma, were unexpectedly strong. To find out why, the researchers conducted follow-up experiments that examined the cell signals involved in neuroligin-3’s role in the division of glioma cells, which demonstrated that neuroligin-3 activates multiple cancer-promoting signaling pathways and also increases the expression of genes involved in cell proliferation, promotion of malignancy, function of potassium channels and synapse function. The researchers now believe that neuroligin-3 is more than just a gatekeeper of glioma cell division, though further research is needed to clarify its exact role, Prof. said.

The team also explored whether blocking neuroligin-3 has therapeutic potential for treating gliomas. Using mice with normal neuroligin-3 brain signaling and human high-grade gliomas, the researchers tested whether two inhibitors of neuroligin-3 secretion could stop the cancers’ growth. One of the inhibitors has never been tested in humans, but the other has already reached phase-2 clinical trials as a potential chemotherapy for other forms of cancer outside the brain.

Both inhibitors significantly reduced glioma growth during a short-term trial, suggesting that the strategy of inhibiting neuroligin-3 secretion may help human patients.

‘Clear path forward for therapy’

“We have a really clear path forward for therapy; we are in the process of working with the company that owns the clinically characterized compound in an effort to bring it to a clinical trial for brain tumor patients,” Prof. said. Inhibition of neuroligin-3 will not represent a cure for high-grade gliomas, she cautioned, since it does not kill the cancer cells. Ultimately, she hopes to combine it with other treatment strategies against the tumors.

“We will have to attack these tumors from many different angles to cure them,” Prof. said. But given how devastating the tumors are, the possibility of using neuroligin-3 inhibition to slow tumor progression is a hopeful development, she added. “Any measurable extension of life and improvement of quality of life is a real win for these patients.”

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Cell`s ‘biological clock’ may harbour cancer cure

Scientists are targeting cell's 'biological clock' in order to find a way to get rid of cancer cells.

UT Southwestern Medical Center researchers found that a small molecule 6-thio-2'-deoxyguanosine could stop the growth of cancer cells in culture and decrease the growth of tumors in mice, and have targeted telomeres with 6-thiodG, which takes advantage of the cell's 'biological clock' to kill cancer cells and shrink tumour growth.

Dr. Jerry W. Shay, Professor and Vice Chairman of Cell Biology at UT Southwestern, said that they observed broad efficacy against a range of cancer cell lines with very low concentrations of 6-thiodG, as well as tumour burden shrinkage in mice.

6-thiodG acts by targeting a unique mechanism that is thought to regulate how long cells can stay alive, a type of aging clock. This biological clock is defined by DNA structures known as telomeres, which cap the ends of the cell's chromosomes to protect them from damage, and which become shorter every time the cell divides. Once telomeres have shortened to a critical length, the cell can no longer divide and dies though a process known as apoptosis.

Cancer cells are protected from this death by an RNA protein complex called telomerase, which ensures that telomeres do not shorten with every division. Telomerase has therefore been the subject of intense research as a target for cancer therapy. Drugs that successfully block its action have been developed, but these drugs have to be administered for long periods of time to successfully trigger cell death and shrink tumors, leading to considerable toxicities. This outcome is partially because cells in any one tumor have chromosomes with different telomere lengths and any one cell's telomeres must be critically shortened to induce death.

6-thiodG is preferentially used as a substrate by telomerase and disrupts the normal way cells maintain telomere length. Because 6-thiodG is not normally used in telomeres, the presence of the compound acts as an 'alarm' signal that is recognized by the cell as damage. As a result, the cell stops dividing and dies.

Telomerase is an almost universal oncology target, yet there are few telomerase-directed therapies in human clinical trials, researchers noted.

Importantly, unlike many other telomerase-inhibiting compounds, the researchers did not observe serious side effects in the blood, liver and kidneys of the mice that were treated with 6-thiodG.
Dr. Shay said that they believe this small molecule would address an unmet cancer need in an underexplored area that would be rapidly applicable to the clinic.

The paper is published in the journal Cancer Discovery.


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Cell's 'biological clock' may be key to cancer cure

UT Southwestern Medical Center researchers found that a small molecule 6-thio-2'-deoxyguanosine could stop the growth of cancer cells in culture and decrease the growth of tumors in mice, and have targeted telomeres with 6-thiodG, that takes advantage of the cell's 'biological clock' to kill cancer cells and shrink tumor growth.

Dr. Jerry W. Shay, Professor and Vice Chairman of Cell Biology at UT Southwestern, said that they observed broad efficacy against a range of cancer cell lines with very low concentrations of 6-thiodG, as well as tumor burden shrinkage in mice.

6-thiodG acts by targeting a unique mechanism that is thought to regulate how long cells can stay alive, a type of aging clock. This biological clock is defined by DNA structures known as telomeres, which cap the ends of the cell's chromosomes to protect them from damage, and which become shorter every time the cell divides. Once telomeres have shortened to a critical length, the cell can no longer divide and dies though a process known as apoptosis.

Cancer cells are protected from this death by an RNA protein complex called telomerase, which ensures that telomeres do not shorten with every division. Telomerase has therefore been the subject of intense research as a target for cancer therapy. Drugs that successfully block its action have been developed, but these drugs have to be administered for long periods of time to successfully trigger cell death and shrink tumors, leading to considerable toxicities. This outcome is partially because cells in any one tumor have chromosomes with different telomere lengths and any one cell's telomeres must be critically shortened to induce death.

6-thiodG is preferentially used as a substrate by telomerase and disrupts the normal way cells maintain telomere length. Because 6-thiodG is not normally used in telomeres, the presence of the compound acts as an 'alarm' signal that is recognized by the cell as damage. As a result, the cell stops dividing and dies.

Telomerase is an almost universal oncology target, yet there are few telomerase-directed therapies in human clinical trials, researchers noted.

Importantly, unlike many other telomerase-inhibiting compounds, the researchers did not observe serious side effects in the blood, liver and kidneys of the mice that were treated with 6-thiodG.
Dr. Shay said that they believe this small molecule would address an unmet cancer need in an underexplored area that would be rapidly applicable to the clinic.

The paper is published in the journal Cancer Discovery.

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New compound that kills cancer cells found

A small new molecule that can kill cancer cells and shrink tumour growth by targeting the 'biological clock' has been discovered.

Researchers at the University of Texas Southwestern Medical Centre in the US found that the molecule called 6-thiodG could stop the growth of cancer cells in culture and decrease the growth of tumours in mice.

"We observed broad efficacy against a range of cancer cell lines with very low concentrations of 6-thiodG, as well as tumour burden shrinkage in mice," said Dr Jerry W Shay, Professor and Vice Chairman of Cell Biology at UT Southwestern.

6-thiodG acts by targeting a unique mechanism that is thought to regulate how long cells can stay alive, a type of ageing clock.

This biological clock is defined by DNA structures known as telomeres, which cap the ends of the cell's chromosomes to protect them from damage, and which become shorter every time the cell divides.

Once telomeres have shortened to a critical length, the cell can no longer divide and dies through a process known as apoptosis.

Cancer cells are protected from this death by an RNA protein complex called telomerase, which ensures that telomeres do not shorten with every division.

Telomerase has therefore been the subject of intense research as a target for cancer therapy.

Drugs that successfully block its action have been developed, but these drugs have to be administered for long periods of time to successfully trigger cell death and shrink tumours, leading to considerable toxicities.

This outcome is partially because cells in any one tumour have chromosomes with different telomere lengths and any one cell's telomeres must be critically shortened to induce death.

6-thiodG is preferentially used as a substrate by telomerase and disrupts the normal way cells maintain telomere length.

Because 6-thiodG is not normally used in telomeres, the presence of the compound acts as an 'alarm' signal that is recognised by the cell as damage. As a result, the cell stops dividing and dies.

"Using telomerase to incorporate toxic products into telomeres is remarkably encouraging at this point," said Wright.

"Since telomerase is expressed in almost all human cancers, this work represents a potentially innovative approach to targeting telomerase-expressing cancer cells with minimal side effects on normal cells," said Shay.

The research appears in the journal Cancer Discovery.
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