The success of current childhood cancer treatment is built on decades of combining different therapies that work together to improve outcomes. This includes chemotherapy and radiation therapy, which remain essential and have been used alongside many other therapies to drastically improve survival rates.
These combinations have resulted in cures for some patients, but the children who do survive face long-term side effects, and other cancers still have unacceptably low survival rates.
We aim to build on past successes by designing smarter, more modern treatment combinations that are both more effective and less toxic, taking a synergistic approach, where the combined effect is more effective than each therapy alone.
By pairing traditional treatments with new, targeted therapies we hope to make cancer cells more vulnerable while sparing healthy cells.
Our researchers are leading efforts to find these powerful combinations. Using world-class preclinical models, we are designing and testing new treatment combinations to understand whether we can identify drugs with strong synergies, add new drugs to existing treatments, develop entirely new combinations for cancers with the lowest survival rates, and design approaches that reduce long term side effects in survivors.
Current research areas
Immunotherapy combinations
We are uncovering why immunotherapy works differently in young children compared to adults, and using these insights to develop smarter combination approaches. By understanding the unique biology of children's immune systems, we aim to harness their immune cells more effectively to better target cancer and improve survival for children with the hardest-to-treat cancers.
Personalised therapy combinations
Using world-class preclinical models, our researchers are identifying innovative ways to combine personalised therapies with existing treatments like chemotherapy and radiotherapy to improve outcomes for children with cancer. These combinations aim to boost the effectiveness of current therapies by homing in on specific vulnerabilities in cancer cells and attacking them. This potentially allows doctors to use lower doses without sacrificing outcomes and reduce the burden of long-term side effects for young patients and survivors.
Potential benefits
By designing modern, carefully matched treatment combinations, we aim to:
- Improve survival for children with hard-to-treat cancers
- Reduce the long-term side effects caused by traditional treatments
- Create safer, more precise therapies tailored to each child’s needs
Our goal is to build on past successes and continue developing therapies that work better together.
Research outcomes
In some cases, we have already seen what is possible when new complementary therapies are added to treatment plans.Outcomes for infants under one year of age with Acute Lymphoblastic Leukaemia have remained stagnant over decades, with five-year event-free survival rates less than 40 per cent. A small pilot clinical study that added an immunotherapy called blinatumomab improved outcomes by 30%. While larger trials are needed, this shows the potential of combination therapies.
Key projects
Immunotherapy combinations – T cell exhaustion in paediatric leukaemia
A promising form of immunotherapy called bi-specific T cell engager therapy is less effective in young children than it is in adolescents and adults. We have successfully modelled this age-dependent difference in our world-first paediatric mouse models. We discovered that T cells in young hosts undergo rapid exhaustion, functioning more like sprinters than the long-distance runners seen in adult immune responses.
In collaboration with Professor Ryan Lister's Epigenetics and Genomics group at the Harry Perkins Institute of Medical Research, we will perform single-cell multi-omic profiling to map the molecular and epigenetic landscape underlying this phenomenon. This work aims to identify novel drug targets to prevent T cell exhaustion and develop synergistic combination strategies with T cell engager therapy.
Personalised therapy combinations – Down Syndrome ALL and beyond
Children with Down Syndrome who develop acute lymphoblastic leukaemia (DS-ALL) face particularly poor outcomes. The intensification of current treatments is limited by high rates of serious toxicity. We have identified a gene called DYRK1A as a key driver of leukaemia growth in DS-ALL and demonstrated that a new drug, LCTB-21, blocks it. Notably, this drug is currently in Phase I clinical to assess its tolerability in patients with Down syndrome. In our preclinical laboratory models, we showed that this LCTB-21 is very well tolerated and reduces leukaemia burden but is not sufficient alone to significantly enhance survival.
Here, we will test the efficacy of combining LCTB-21 standard-of-care chemotherapy to reduce leukaemia burden and extend survival across DS-ALL models, optimise the combination scheduling, and evaluate this approach in other poor-prognosis childhood leukaemia subtypes. We aim to deliver a safer and more effective treatment strategy for these high-risk patients.
Targeted therapy combinations – Embryonal brain cancers
Embryonal brain cancers including AT/RT, pineoblastoma, and ETMR primarily affect infants and carry a devastating prognosis. We have identified a drug called elimusertib that makes cancer cells more vulnerable to radiation in high-risk medulloblastoma.
With a paediatric Phase 2 dose now established, we are extending this work to these rare embryonal cancers where new treatment strategies are urgently needed. The laboratory findings from this work will directly inform the design of upcoming international clinical trials, with the goal of improving survival for some of the most vulnerable patients in paediatric oncology.
