Reviving the protector—new tactic against medulloblastoma

June 11, 2018, Emory University

Scientists have a new tactic with potential for fighting medulloblastoma, the most common and most aggressive form of brain tumor in children.

The results are scheduled for publication in Cancer Cell.

Several emerging anticancer treatments are called "epigenetic therapies," targeting the ways cancer cells shut off genes that could restrain their growth. The new tactic revives a protective gene called BAI1, by interfering with a protein that cells use to silence BAI1.

Reactivating BAI1, with a compound that penetrates into the brain, blocks medulloblastoma growth in mice. Senior author Erwin Van Meir, Ph.D., says this compound could be a basis for drug discovery and a valuable tool for attacking other types of cancer as well.

"It was a surprise the molecule we identified was more specific than we thought." Van Meir says. "This opens up a new area in epigenetic therapy."

Van Meir says that the Cancer Cell paper brings together research in his lab over the last 10 years. His team had originally been studying BAI1, because it was silenced in glioblastoma, another seen in adults. They had initially noticed that BAI1 is a regulator of angiogenesis, the process by which tumors attract new blood vessels.

"It turns out this is not actually BAI1's most important function," Van Meir says.

BAI1 is also a "protector" of p53, which has a role in preventing many types of cancer by monitoring DNA damage and sensing other types of stress—p53 is sometimes called "guardian of the genome."

Senior research associate Dan Zhu, Ph.D., the first author of the paper, was able to work out how BAI1 (also known as ADGRB) protects p53: by holding back another protein, Mdm2, which tags p53 for degradation.

In mice, the interactions between BAI1 and other genes linked to weren't clear until Van Meir and his colleagues started looking at models of medulloblastoma.

"Once we delved into medulloblastoma, it became very obvious," he says, adding that targeting BAI1 is likely to be effective across the four molecular sub-varieties of medulloblastoma.

The compound that reactivates the BAI1 gene, called KCC-07, was identified in collaboration with the lab of Bill Nelson at Johns Hopkins. It interferes with MBD2, a protein that binds methylated DNA. Methylation is generally a modification that shuts genes off, and some epigenetic therapies aim to inhibit methylation, such as azacytidine/Vidaza, used against myelodysplastic syndrome. However, inhibiting the process of methylation turns many on or off—targeting just one DNA-binding protein could be more specific, Van Meir says.

KCC-07 could inhibit medulloblastoma growth in cell culture and in mouse models, and "represents a promising chemical scaffold for further drug development," the researchers conclude.

Explore further: From brain tumors to memory: A very multifunctional protein

More information: Cancer Cell (2018). DOI: 10.1016/j.ccell.2018.05.006

Related Stories

From brain tumors to memory: A very multifunctional protein

March 9, 2015
Everything is connected, especially in the brain. A protein called BAI1, involved in limiting the growth of brain tumors, is also critical for spatial learning and memory, researchers have discovered.

Genetic counseling and testing proposed for patients with the brain tumor medulloblastoma

May 9, 2018
Researchers have identified six genes that predispose carriers to develop the brain tumor medulloblastoma and have used the discovery to craft genetic counseling and screening guidelines. The study appears today in the journal ...

In the eye of the medulloblastoma

March 12, 2018
Can genes normally expressed only in the eye be activated in brain tumours? The phenomenon, though surprising, has been observed in certain types of medulloblastoma, paediatric tumours of the cerebellum. Researchers from ...

Promising target for treating brain tumors in children

November 28, 2017
Findings published in Oncotarget offer new hope for children with highly aggressive brain tumors like atypical teratoid/rhabdoid tumor (AT/RT) and medulloblastoma. Previously, the authors of the study have shown that an experimental ...

Combination of medications slows down brain tumours in children

April 9, 2018
In collaboration with a number of American colleagues, researchers from Uppsala University have found an Achilles' heel for the most common form of malignant child brain tumours. By combining two kinds of medicines, it is ...

New pathway identified as a target for precision medicine against a common brain tumor

November 2, 2017
St. Jude Children's Research Hospital scientists have discovered a promising target for precision medicines to block a mechanism that drives several cancers, including about 30 percent of cases of the brain tumor called medulloblastoma. ...

Recommended for you

New drug seeks receptors in sarcoma cells, attacks tumors in animal trials

December 13, 2018
A new compound that targets a receptor within sarcoma cancer cells shrank tumors and hampered their ability to spread in mice and pigs, a study from researchers at the University of Illinois reports.

Surgery unnecessary for many prostate cancer patients

December 13, 2018
Otherwise healthy men with advanced prostate cancer may benefit greatly from surgery, but many with this diagnosis have no need for it. These conclusions were reached by researchers after following a large group of Scandinavian ...

Combining three treatment strategies may significantly improve melanoma treatment

December 12, 2018
A study by a team led by a Massachusetts General Hospital (MGH) investigator finds evidence that combining three advanced treatment strategies for malignant melanoma—molecular targeted therapy, immune checkpoint blockade ...

Researchers use computer model to predict prostate cancer progression

December 12, 2018
An international team of cancer researchers from Denmark and Germany have used cancer patient data to develop a computer model that can predict the progression of prostate cancer. The model is currently being implemented ...

An integrated approach to finding new treatments for breast cancer

December 12, 2018
Unraveling the complexity of cancer biology can lead to the identification new molecules involved in breast cancer and prompt new avenues for drug development. And proteogenomics, an integrated, multipronged approach, seems ...

New insight into stem cell behaviour highlights therapeutic target for cancer treatment

December 12, 2018
Research led by the University of Plymouth and Technische Universität Dresden has identified a new therapeutic target for cancer treatment and tissue regeneration – a protein called Prominin-1.

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.