Solid tumours in children (2023)
Challenge: Develop therapeutics to target oncogenic drivers of solid tumours in children
Cancer remains the leading cause of death by disease in children globally, and progress in the treatment of children with solid tumours (which includes brain tumours) has largely stalled. For those children who relapse, there are fewer treatment options available, meaning the outlook is often poor, and outcomes for some paediatric cancers have not improved in more than 30 years.
Despite advances in understanding the biology of most paediatric solid tumours, standard curative treatment regimens continue to rely on cytotoxic agents, developed decades ago, and often radiotherapy. Such therapies induce an alarming rate of severe late effects, including second malignancies, cardiac, neurologic, and skeletal toxicity, and infertility. Targeted therapeutics are needed to improve outcomes for paediatric cancers.
Barriers and opportunities
Tumours arising in children differ from those occurring in adults. Whereas mutant kinases commonly drive adult cancers and kinase inhibitors have had great impact in the treatment of adult cancers, oncogenic drivers in children’s solid tumours are typically transcription factors and/or epigenetic proteins which have historically been considered “undruggable”. Compounding the biological challenges, drug development in biopharma for paediatric solid tumours has not been prioritised, due to the small market size.
New platforms show promise for targeting transcription factors and epigenetic pathways, including selective protein degraders, molecules that disrupt essential protein-protein interactions and cell selective delivery of oligonucleotides to modulate gene expression.
Questions that could be addressed in this challenge include, but are not limited to:
Can we develop protein degraders that selectively target oncogenes that drive paediatric cancers, and do they regress tumours in preclinical models? Does E3 ligase biology vary between adults' and children's solid tumours?
What are the major resistance pathways for protein degraders in paediatric cancers? What type of protein degrader is most suited for this setting (e.g., molecular glues vs. heterobifunctional degraders) and what targets are susceptible to this approach?
How do degraders compare to emerging small molecules that work by disrupting protein-protein interactions or oligonucleotides? Can we use midsize cyclic proteins to target undruggable targets?
Can we identify targeted therapeutics that should be prioritised for clinical testing in paediatric solid tumours?
What is the toxicity profile of these agents in children?
Vision and Impact
Paediatric cancer drug development is inefficient and resources to develop drugs for paediatric cancers are often rate limiting.
An interdisciplinary and disruptive team capable of discovering, developing, and conducting early clinical testing of novel targeted therapeutic(s) is needed. Members could include cancer biologists, developmental biologists, clinical investigators, animal modellers, and medicinal chemists. Applicants should include a rationale for the age range of the participants in any proposed studies and how this would address the challenge.
Development of effective targeted therapeutics for paediatric solid tumours will improve survival and diminish the lifelong toxicities experienced by survivors of these diseases.
Plain language summary: Why solid tumours in children?
Cancer remains a leading cause of death due to disease among children globally, and outcomes for some childhood cancers have not improved in more than 30 years. Treatments for solid tumours in children still rely on decades-old chemotherapies, and often radiotherapy. Children who must endure these treatments often later experience severe side effects, such as secondary cancers; heart, nervous system and bone toxicity; and infertility.
Childhood tumours are different from those in adults, in that they are often caused by genetic changes (mutations) affecting different types of proteins from those in adults. The proteins that drive these cancers have historically been considered “undruggable” targets, and progress in effectively targeting these proteins has stalled.
This challenge seeks to find ways to ‘drug the undruggable’, by developing therapies that target the drivers of solid tumours in children. By developing effective targeted therapies for children with solid tumours, we should be able to improve survival and reduce the lifelong side effects caused by existing treatments.