Venetoclax has been approved by the Australian Therapeutics Goods Administration (TGA) to treat an adult leukaemia. Could it one day treat childhood leukaemia?

The drug Venetoclax, discovered and developed at Melbourne’s Walter and Eliza Hall Institute, kills cancer cells by targeting and disabling a protein called BCL-2. In clinical trials it produced remarkable results in adult patients with relapsed or refractory, ie hard-to-treat, chronic lymphocytic leukaemia (CLL). CLL affects 1300 adult Australians every year and is the most common subtype of adult leukaemia. The drug was fast-tracked for approval in the US last year.

Like many drugs, the journey of Venetoclax from lab bench to hospital bedside has stretched over decades. In 1988 scientists at the Walter and Eliza Hall Institute identified the protein BCL-2 as helping cancer cells to survive. Since then, scientists worldwide have been searching for a way to inhibit its activity. Nearly 30 years later, they’ve reached their destination and Venetoclax is available for clinical use.

Professor David Huang’s team at Walter and Eliza Hall Institute was involved in the drug’s development and it won them an Australian Museum Eureka Prize last year.

“I think it is incredibly exciting for us to see the many years of hard work into a difficult scientific problem being developed into a new drug and eventually benefiting patients,” Professor Huang said.

Could Venetoclax be used to treat childhood leukaemia too?

While it affects adults in greater numbers, leukaemia is also the most common childhood cancer. Overall survival rates for children are now around 90%, but some ‘high-risk’ leukaemia subtypes have a much lower survival rate, often failing to respond to conventional chemotherapy. On the plus side, they contain specific molecular changes that could be treatable by new, targeted therapies.

Research published last year by Professor Huang and our own Professor Richard Lock showed Venetoclax holds promise for infants, i.e. children under one year old, with a high-risk subtype of leukaemia called mixed lineage leukaemia-rearranged infant ALL (MLLr-ALL). This subtype produces BCL-2, the molecular target of Venetoclax. Professor Lock’s research team showed that Venetoclax, used on its own, is effective against MLLr-ALL.

Prof David Huang (Walter and Eliza Hall Institute) with Prof Richard Lock
Prof David Huang (Walter and Eliza Hall Institute) with Prof Richard Lock

“Venetoclax is not as broadly active for the most common paediatric leukaemia as it is in adult CLL, but some paediatric high-risk subtypes are more susceptible to the drug than others,” notes Professor Lock.

Clinical trials in children are planned. With further testing, this Australian-developed drug could be used to treat infants in a personalised medicine approach. Research will determine whether combining Venetoclax with other drugs will make it even more effective.

Targeting genetic changes in cancer

Venetoclax is one of the new generation of targeted cancer therapies. Unlike conventional chemotherapies, which are generally toxic, and often produce debilitating side effects, targeted therapies aim to kill cancer cells while leaving healthy cells untouched. They do this by targeting specific genetic changes in cancer cells.

Blood cells from leukaemia patient
Blood cells from leukaemia patient

Scientists use the term ‘gene drivers’ to describe the genetic changes that help cancer cells survive and proliferate. The interplay of gene drivers and the proteins they code for can be complex, and varies for each type of cancer, and in fact, for each cancer patient.

Not only that, cancers in children are by nature different to cancers in adults and often need different treatments. For instance, many adult cancers are caused by environmental factors or lifestyle choice. Children’s cancers are more likely the result of genetic factors and other yet-to-be-determined aspects of the early life environment. This may explain why Venetoclax, although it targets a gene driver common to adult CLL and the MLLr-ALL subtype of childhood leukaemia, is less effective in the latter.

Personalising cancer treatment

As more gene drivers and their associated proteins are identified, and new drugs are developed to specifically target them, the weapons in oncologists’ arsenals are increasing in number and precision. Venetoclax is the latest addition.

This tailored approach to cancer treatment, brought on by the genomics revolution, is called ‘personalised’ or ‘precision’ medicine, and will change the face of healthcare. The identification and targeting of gene drivers in individual patient’s cancer cells is an integral part of the Zero Childhood Cancer personalised medicine program led by us and Sydney Children’s Hospitals Network. With more research and testing, Venetoclax may well turn out to be part of this personalised approach to treat some of childhood cancer’s more aggressive subtypes.

Read about the research published by Profs Huang and Lock in the prestigious journal Blood.



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