New cancer cell discovery sheds light on childhood blood cancer  

The discovery of new drug targets is always a big win for cancer research, especially when treatment resistance remains a major challenge. A new type of cancer cell containing a gene called ZBTB16 has been discovered that could potentially move the needle for therapeutic research for an aggressive form of blood cancer that affects children. 

ZBTB16: study finds cancer cells with switch 

Mapping how T-cell leukemia develops, a team of researchers at the Wellcome Sanger Institute, Great Ormond Street Hospital, University College London, and Addenbrooke’s Hospital in the U.K. identified a new subtype of white blood cells called T-cells that are cancerous being responsible for patients not responding well to current treatments. The scientists believe that these cells contribute to the high death rate in children with T-cell leukaemia. 

Also called T-cell acute lymphoblastic leukemia (T-ALL), it is a form of acute lymphoblastic leukemia (ALL) that originates in stem cells in the bone marrow. When these normal stem cells mutate, they become cancerous, multiplying and producing many ALL cells. In T-ALL, the cells that mutate are immature T-cells in the bone marrow. 

Accounting for about 20% of all ALL cancers, according to a paper published in Nature, T-ALL survival statistics have improved over the years. However, treatment failure and resistance are higher than in other forms of blood cancers.  

“In T-cell leukaemia, we cannot predict which children will or will not respond to initial treatment,” Sam Behjati, co-senior author at the Wellcome Sanger Institute and honorary consultant paediatric oncologist at Addenbrooke’s Hospital, told Labiotech. 

That’s why the discovery of these cancerous cells, and more importantly, the switch responsible for their development can help choose the right treatment for patients. 

“Our findings indicate that there are two fundamentally different types of T cell leukaemia. Normal T cells come in two different flavours – conventional and unconventional. During development, there is a switch called ZBTB16 which determines whether a developing T cell evolves into a conventional or unconventional T cell,” Behjati told Labiotech. “What our findings show is that treatment-resistant leukaemia T cells resemble unconventional cells and that they utilise the very same switch, ZBTB16.” 

Based on 58 samples from children with T-ALL, the scientists did a genomic analysis to find out how these abnormal T cells came about. This is when they detected that some genes like ZBTB16 were more active in these cancer cells than other ones. Plus, certain treatments had no effect on these genes, and they continued to be activated. They then found that ZBTB16 can be turned on at any point during T-cell development. 

T-cell leukemia particularly hard to treat 

Unlike in B-cell leukemia where doctors are more likely to correctly predict whether a treatment will work for a child and tailor them accordingly, Behjati pointed out that this isn’t in the case for children affected by T-cell leukemia. This results in children going through weeks of chemotherapy and then having to do tests to see if there are cancer cells left in the bone marrow.  

As chemotherapy comes with several side effects, it would help to be certain whether it will work in the first place. Moreover, it would mean other treatment options can be sought sooner, cutting chances of disease progression.  

And as there is currently no way to know which T-ALL cancers are high risk when patients get diagnosed, the discovery of these cells points to new avenues to both diagnose and treat the aggressive cancer quicker. 

One patient who was part of the study was three-year-old Jacob, who was diagnosed with T-ALL after he was taken to the emergency room when his parent noticed he had bruises on his arm and was vomiting a year ago. Following a blood test that showed a really high white blood cell count of 850 – the normal range being between five and 15 – he was put on chemotherapy. 

“Since Jacob was diagnosed with leukaemia last December, it’s been a complete whirlwind of a journey,” said Jacob’s parents, Alexandria and Animesh, from Essex in the U.K. 

While Jacob responded well to the initial chemotherapy despite having an aggressive cancer and did not require a bone marrow transplant, the wait to find out whether the treatment would work at all was gruelling. 

“While we were fortunate that Jacob responded really well to his chemotherapy, we spent a number of months waiting for his bone marrow test results to come back to confirm that he could continue on a chemotherapy-only protocol rather than having to try another treatment, as the tests have to be done at specific timepoints,” said Jacob’s parents. 

ZBTB16 switch discovery: no more trial-and-error with chemotherapy? 

Indeed, now that the role of ZBTB16 in the development of this type of cancer is clear, how a child responds to a treatment could be predicted on the day of their diagnosis. 

“Research like this is so important to help move towards a future where children can have the right cancer treatment more quickly,” they said. “If we had known from the beginning that this would likely be the case it would have provided us with some reassurance in what was a difficult time, and we truly hope that these new developments will help other parents who find themselves in the same position.” 

Scientists like Behjati want the same for children like Jacob – to be able to provide clarity during diagnosis about what treatment route to take. 

“This would enable us to tailor treatment – give children who are likely to do well less treatment and vice versa,” said Behjati. “We may be able to design therapies that specifically target treatment resistant cells.” 

For instance, immunotherapies could be created to target this specific T-ALL cancer cell, giving way to more effective treatments with fewer side effects since the medicines will be better targeted. 

“The discovery of this new type of cancerous T-cell is one of the most exciting findings of my career so far and warrants urgent investigation so that it can be translated into clinical impact as soon as possible,” said Behjati. “For example, targeting these newly discovered cancer cells could lead to effective therapies for T-cell leukaemia that currently don’t respond to first-line treatment, something that children and adults living with this cancer urgently need.”     

T-ALL cancers: massive jump in survival rate in recent times  

Acute lymphoblastic leukemia research has seen progress over the years, so much that the bleak 3% survival rate for children 50 years ago has dramatically improved to an 85% cure rate now, according to a report by Blood Cancer United. Cure rates for adults, however, are far from close; around 50%, according to the Leukemia Research Foundation. 

Breakthroughs in CAR-T therapy have helped clear the path to treating B-cell ALL, however, taking on T-cell ALL remains tricky since CAR-T cells and the cancer cells are both T-cells, and for the body to be able to differentiate between the two is complicated, although research is ongoing.  

Recently, scientists managed to distinguish cancerous T-cells from the healthy ones, and they created a new therapy derived from CAR-T cells designed to target two specific markers. The candidate was effective in preclinical trials, warranting studies to be carried out in the clinic. The research was conducted by the Josep Carreras Leukaemia Research Institute and the Aragon Health Research Institute in Spain. 

With the unearthing of the cells containing the activated ZBTB16 gene that spurs the uncontrolled growth of cancerous T-cells, immunotherapies aside from CAR-T therapy could be tested too, giving way for more approaches to tackle treatment-resistance in this deadly type of cancer.