Advancing new therapies against germ cell tumours in children and young adults – decreasing side effects, overcoming resistance

Since the introduction of cisplatin as a first-line therapy for germ cell tumours (GCTs) in the 1980s, five-year survival rates have exceeded 90%. While survival rates are high, these are associated with long term toxic side-effects, which is particularly relevant to a young patient cohort. Additionally, chemoresistance is relatively common, leading to ~65 deaths each year in the UK (and around 10,000 globally).

This pioneering early success has stymied further progress, with the consequence that toxic side-effects and resistance associated with current therapy have remained unaddressed for the past 40 years. While several clinical trials have been initiated for new agents, none have been substantially safer or more effective than first line therapeutic regimes developed in the 1980s.

We have approached this challenge through a new lens: by investigating why GCTs are well treated, with the goal of identifying new vulnerabilities. Our genetic studies in mice and cell culture analyses have converged on the BCL2 family of proteins, for which several drugs are being tested in other cancer contexts. Our goal is to progress our promising laboratory data into animal xenograft models as an immediate precursor to human clinical studies.

The team’s proposal aims to advance a promising new therapeutic approach against germ cell tumours from the bench, towards the clinic and patient benefit. The new approach has potential to decrease side-effects of current treatments and tackle resistant disease.

The team’s goal is to provide sufficient evidence of effectiveness in advanced tumour models that can be used as the foundation for first-in-human studies within 5 years.

If our studies are successful, they will provide in-principle evidence that supports further clinical consideration. The likely next step would be as an additional treatment in chemoresistant disease, where no reliable therapies currently exist.  

Given the high cure rate for GCTs, any testing of a new first-line therapy would need to carefully evaluate our approach in phased de-escalation studies. If our approach is successful at each step, it would likely bring about targeted therapies that are kinder and gentler for the young patient cohort, by reducing the dose of cisplatin and limiting side-effects that include an elevated risk of secondary cancers, infertility, deafness, and heart disease.

For individuals with a poor prognosis, this approach could yield a life-saving therapy, which currently claims around 65 lives each year in the UK.