Potential treatment advance for aggressive childhood cancer revealed

Research by Australian scientists could pave the way for a new treatment for a currently incurable childhood brain cancer called Diffuse Intrinsic Pontine Glioma, or DIPG. DIPG affects about 20 children in Australia each year and is a devastating disease with an average survival time of just nine months from diagnosis.

The mouse model research, led by scientists at the Children’s Cancer Institute and UNSW and published this week in Cell Reports, offers a new therapeutic approach to treating DIPG using a new anti-cancer drug.

The new drug, CBL0137, is an anti-cancer compound developed from the anti-malarial drug quinacrine. The researchers found that CBL0137 directly reverses the effects of the major genetic factors in DIPG in mice and has a profound effect on DIPG tumor models. They also found that CBL0137 is even more effective when combined with a second drug, panobinostat, a new type of drug known as a histone deacetylase (HDAC) inhibitor. When used in combination, the two drugs have been shown to act synergistically, each enhancing the effects of the other against DIPG.

UNSW Conjoint Associate Professor David Ziegler, group leader at Children’s Cancer Institute and pediatric oncologist at Kids Cancer Center, Sydney Children’s Hospital, said there was a desperate need for a new and more effective way to treat DIPG.

“Many different types of treatments have been tried for DIPG over the years, but none have so far been shown to be effective in clinical trials in children with the disease,” he said. Part of the problem is that the genetic driver in DIPG is a master gene that controls thousands of other genes. Until now, we didn’t know how to turn it off. Our data shows that CBL0137 reverses the effects of this master gene and then shuts down the growth of the DIPG tumor cells. “

In the recently published study, A / Professor Ziegler and his colleagues from the Children’s Cancer Institute built on previous research from the institute that found CLB037 to be effective against neuroblastoma. Using a similar approach with DIPG, the group confirmed that CBL0137 disrupts the growth of DIPG tumors by inhibiting an important molecule known as FACT (needed for DNA transcription, replication and repair). They found that FACT binds to the main genetic driver in DIPG – a mutation called K27M. By treating DIPG cells with CBL0137, they were able to target this gene and stop the growth of tumor cells. They then tested CBL0137 in ‘patient-derived xenografts’ – mice specially bred to grow DIPG cells taken directly from children with the disease – showing that it effectively penetrated the blood-brain barrier and increased survival time.

When the researchers added panobinostat to the mix, they found that the CBL0137-panobinostat combination was even more effective at killing DIPG cells and further improved the survival time of mice with DIPG.

“K27M is the Achilles heel of DIPG tumor cells,” said associate professor Ziegler. “The finding that CBL0137 acts indirectly against this genetic driver is very exciting and gives us great hope for this treatment strategy.”

A / Prof Ziegler will lead an international clinical trial of CBL0137 for children with DIPG, which will be opened in the best pediatric hospitals in the US and Australia. Plans to initiate the study are boosted by the fact that CBL0137 has recently successfully completed testing in Phase I clinical trials in adults with solid tumors.

This work was supported by grants from the National Health and Medical Research Council, Cancer Institute NSW, the DIPG Collaborative, The Cure Starts Now, Kid’s Cancer Project, Cure Brain Cancer Foundation, Levi’s Project, and the Benny Wills Brain Tumor Research Fund.

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