International Team of Researchers Revives Hopes For Future Leukemia Treatment

An international collaboration of researchers has managed to find an avenue for safer treatment of a specific type of leukemia called T-ALL. This form of leukemia mainly affects children and is fatal if left untreated.

Their research opens up new exciting avenues for developing effective treatments in the not too distant future. The findings were published in this week's edition of Science Translational Medicine. 

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Who is the research team?

The international team included researchers from VIB-KU Leuven, Belgium, the UK Dementia Institute and the Children's Cancer Institute in Australia. They have managed to refine a therapeutic avenue for treating T-ALL that had been abandoned due to its severe side effects. 

Their new approach is very effective and, more importantly, safe to use on mice and human cancer cells.

What is T-ALL?

T-ALL stands for T-cell acute lymphoblastic leukemia. This is a distinct variety of cancer that is characterized by the presence of a lot of immature white blood cells. 

"T-ALL mainly affects children and is rapidly fatal if left untreated. Current chemotherapy is very effective but causes long-term side effects, so there is an urgent need for less toxic targeted therapies for these young patients," explains leukemia expert Prof. Jan Cools at VIB-KU Leuven.

One of the main biological pathways involved in T-ALL is something called Notch signaling. This is a highly conserved cell signaling system present in most multicellular organisms.

Previous research into T-ALL was geared toward blocking an enzyme called gamma-secretase which plays a major role in the Notch process. Unfortunately, these gamma-secretase inhibitors proved to be too toxic for clinical use because of side effects in a variety of healthy tissues.

For this reason, it was later abandoned, until now. 

But the blocking of gamma-secretase is also important for Alzheimer's disease. This is because it is also involved in the processing of amyloid-beta, which is linked to neurodegeneration. 

"It is important to realize that gamma-secretase is actually a complex consisting of four protein subunits, two of which exists in very different versions," says Alzheimer specialist, and co-lead in the current study, Prof. Bart De Strooper (VIB-KU Leuven, UKDRI).

"Clinical trials have been performed with broad-spectrum, non-selective inhibitors that target all different versions of the complex equally. We wanted to explore whether inhibition of specific versions could fine-tune the treatment and reduce side-effects."

What did they find out?

By focussing on gamma-secretase in their study, they found that there appeared to be varying amounts of two different types of the complex in leukemia cells versus healthy cells. Naturally, this led them to ponder whether inhibiting only the leukemia-specific version of the complex would prove to be a safer, yet still effective treatment option. 

"We saw that targeting only one type of complex was both effective and safe in mouse models and in leukemia cells from T-ALL patients," explained Dr. Roger Habets (co-author of the study).

"Not only could we stop leukemia from growing, but we also found no signs of the toxicity that usually plagues this class of drugs."

The findings of the study have revived hopes that an effective treatment for leukemia could be just around the corner. 

"Historically, these types of drugs have had very limited success, since patients did not tolerate the side effects in normal tissues. We provide the first proof of concept that selective targeting of a specific version of the gamma-secretase complex is effective and safe, suggesting this strategy's potential for translation," said another co-author of the study, Dr. Charles de Bock. 

"If this approach would indeed work for patients with T-ALL, this could open up the door for other types of cancer as well. Safe, selective gamma-secretase inhibition might even be useful as an additional therapy in a variety of other disorders in which Notch signaling is deregulated," added Jan Cools and Bart De Strooper. 

This all sound very promising for leukemia patients but a word of warning before you get too excited. The study is only a breakthrough in research, not in medicine. 

It opens up new avenues for effective treatments in the future but they still need to be developed and extensively tested. This can take years. 

The study is titled "Safe targeting of T-cell acute lymphoblastic leukemia by pathology-specific NOTCH inhibition" and was published this month in Science Translational Medicine 2019.