Finding effective treatments for the most common childhood cancer
By Cancer Council NSW
Professor Richard Lock has been a cancer biologist for over 30 years and specialises in leukemia research. Cancer Council NSW has played an important role in his research journey with his first major Australian grant funded by the organisation.
Since that first grant his research has advanced, and in 2011 he was awarded another Cancer Council NSW grant to discover and test new drugs that could target and kill acute lymphoblastic leukaemia (ALL) cells. Five years after this grant ended, we caught up with Professor Lock to see how his innovative research had progressed.
“The cure rate for infant ALL patients is only 50-60% and most infants who do survive are often faced with long-term side effects. This really is a problematic disease and we desperately need more effective treatments for infants with ALL and treatments which don’t leave them with major side effects”.
Professor Lock had previously set out to create a preclinical model to study the most common paediatric cancer, ALL. Once the model had been established and validated, he could then use this model to test drugs that were already in the cancer field to see how effective these were at killing paediatric ALL cells. He already knew that one of the ways cancer cells were able to stay alive was by avoiding their normal programmed pathway to naturally die. Professor Lock and his team wanted to find drugs that would target and kill the cells that avoided this usual pathway to cell death but also cause minimal side effects for the patient.
Leukemia cells can avoid cell death by upregulating to a family of proteins, called Bcl-2 family proteins. Some of these proteins are known as ‘pro-survival’ proteins and others are known as ‘pro-death’ proteins. These two types of proteins interact with each other and play a pivotal role in deciding whether a cancer cell will survive or die. What Richard’s team knew was if they could use a drug which can mimic the pro-death proteins, and stop pro-survival proteins from working, then this would trigger the cancerous cells to enter the pathway and die – and this is what he did.
“Using drugs that are able to mimic the pro-death proteins can stop the pro-survival proteins from working”.
He tested two different drugs, Navitoclax and Venetoclax. The first was able to target three different pro-survival Bcl-2 proteins and the second targeted a single Bcl-2 protein, commonly found in infants with a high-risk subtype of ALL and showed impressive activity against this subtype.
“Determining which subtype of paediatric ALL might respond better to these drugs can help us understand why one patient responds to treatment and another patient doesn’t.”
Thanks to the funding received from Cancer Council NSW, Professor Lock used his established preclinical model to make significant progress in understanding how these drugs work, which patients could benefit from them, and identifying which new drugs should be prioritised into the clinical setting.
He discovered that Venetoclax was very effective against a high-risk subtype of paediatric ALL. Excitingly, Navitoclax and Venetoclax are now being used in three clinical trials. The trials focus on the effects that these two drugs in combination with chemotherapy will have on patients with relapsed ALL. Infants with relapsed ALL present as a significant challenge due to limited treatment options. The results from the clinical trials will hopefully provide a new treatment approach for infants with ALL.
Moving forward with this research
Looking towards the next generation of drugs
Many ALL children who survive into adulthood will have been exposed to drugs that cause long-term side effects. Professor Lock’s team is very keen to discover drugs which are specialised to each individual patient, producing fewer and minimal side effects. They are currently investigating a new generation of drugs that can trigger the programmed cell death pathway by targeting different members of the Bcl-2 family. They want to identify drugs that only target cancer cells and not healthy cells, and plan to progress these into clinical trials for children with high-risk leukaemia.
“A cure is not enough – we want to reduce the long-term side effects of treatment”.
Real time pre-clinical drug testing
There are many different subtypes of ALL meaning that a ‘one-size fits all’ treatment approach isn’t good enough because it will not work for every patient. The Zero Childhood Cancer PRISM clinical trial is running in eight paediatric centres across Australia to focus on personalised treatment. As part of this trial, Professor Lock is using his preclinical leukaemia model to identify the mutations present in high-risk ALL patients and then personalise the treatment the patient will receive. The Bcl-2 drugs are being tested in this personalised medicine trial with the aim to feedback to doctors in real time providing more treatment options to benefit the patient.
“If a patient walks in and they’ve got less than a 30% likelihood of surviving, we take their cancer cells and test them to identify what mutations they have in order to tailor individual therapies for these patients”.
The results from this clinical trial could transform the lives of ALL patients – especially those who have not responded to conventional therapy and have very limited treatment options. “The goal is to identify drugs that are effective and specifically target cancer cells, replacing the current drugs which work but are very toxic and leave long lasting side effects”.