Studies in cell and animal models reveal insights into cancer cells vulnerability that could lead to new strategies against brain cancers.

Here, a confocal micrograph shows DIPG cells, grown from patient cells, in culture.

The cells are expressing several proteins, including: DAPI (blue, in the cell nuclei); vimentin (red, a protein marker of neural stemprecursor cells and glioma cells); and Nestin (green, also a protein marker of neural stemprecursor cells and glioma cells).

Scientists at the National Institutes of Health, Stanford University, California, and Dana-Farber Cancer Institute, Boston, identified a drug pair that worked together to both kill cancer cells and counter the effects of a genetic mutation that causes the diseases.

Their studies also uncovered a previously unrecognized vulnerability in the cancer cells that scientists may be able to exploit to develop new strategies against the cancer and related diseases.

The results were published Nov.

Science Translational Medicine.

Most cases of DMG are caused by a specific mutation in histone genes.

DNA wraps around histones to form chromatin, which packages DNA in the nucleus.

How DNA winds and unwinds around histones is influenced by enzymes, including histone deacetylases.

These enzymes add or remove chemical tags, which indirectly controls if genes are turned on or off.

While panobinostat is already in early clinical testing in DIPG patients, its usefulness may be limited because cancer cells can learn to evade its effects.

So Monjes team wanted to identify other possible drugs and combinations of them that could affect the cancer.

Weve known for a long time that we would need more than one treatment option for DIPG.

The challenge is prioritizing the right ones when there are thousands of potential options.

Were hopeful that this combination will help these children.

Thomas and his team used NCATS drug screening expertise and matrix screening technology to examine drugs and drug combinations to see which ones were toxic to DIPG patient cells.

Scientists can examine the most promising single drugs and combinations, determine the most effective doses of each drug and learn more about the possible mechanisms by which these drugs act.

They focused on agents that could both kill DIPG cells and cross the brains protective blood-brain barrier, a necessity for a drug to be effective against DIPG in patients.

The team then tested the most effective single agents in various combinations.

NCATS was designed to bring together biologists, chemists, engineers and data scientists in a way that enables these technically challenging studies.

Proteasome inhibitors block cells normal protein recycling processes.

The panobinostat-marizomib combination was highly toxic to DIPG cells in several models, including DIPG tumor cell cultures that represented the main genetic subtypes of the disease and mice with cells transplanted from patient tumors.

The combination also reduced tumor size in mice and increased their survival.

A similar response was found in spinal cord and thalamic DMG models developed from cells grown in culture from patient cells.

Neuro Dmg