Pediatric vs Adult Cancers: Why are children not just small adults?

The goal of the VAGABOND network is to advance our understanding of pediatric cancers and develop better treatments for children suffering from them. But what is so unique about childhood cancers that requires a consortium of dedicated research? Although tumors develop following a similar pattern in adults and children, pediatric cancers display characteristics that significantly differentiate them from their adult counterparts. In this post, we will address the challenges involved in treating pediatric cancers and how the VAGABOND consortium is working to overcome them.

Cancer is rare in children
The first difference is that cancer is vastly more common in adults than in children. Within the European Union, only 21 in every 100,000 children and adolescents were diagnosed with cancer in 2020. In contrast, these numbers rise to around 800 in every 100,000 when we talk about adult cancers1. As a result of this – fortunately – low prevalence of cancer among children and adolescents, studying pediatric cancer is a challenging task. Thus, collaborative efforts like VAGABOND are essential to improve our understanding of these diseases. In our network, the tight connection between academic and non-academic partners (e.g. pharmaceutical companies) contributes to the swift translation of our findings from the bench to the bedside.

Pediatric cancers show distinct localization and genetics
Besides being rarer, pediatric cancers generally appear in different locations than the adult forms. The most common cancers in adults affect the breast, intestines, prostate, or lungs. However, pediatric cancers often occur in the blood, lymph nodes, central nervous system or soft tissues (1). Moreover, some types of cancer are almost exclusively pediatric, such as neuroblastoma (2) or retinoblastoma (3).

Figure 1: Most common cancer types in adults (left) and children (right). Source: ECIS – European Cancer Information System (https://ecis.jrc.ec.europa.eu/)

The general view in the field of oncology is that cancers develop and evolve by accumulation of genetic mutations, with environmental factors being a major contributor to this process. However, the picture seems to be more complex in pediatric cancers. Childhood cancers are less influenced by environmental factors – such as tobacco or alcohol consumption – which play a major role in adult cancers, as they arise during development or childhood. Partially due to this early onset, cancers in children show in average 14 times less mutations than in adults. In almost half of the cases, these mutations affect genes that are not mutated in adults and in a fraction of patients no genetic aberration has been found at all (4, 5). This genetic quietness, despite not affecting the capacity of the tumors to evolve, reduces the molecular targets towards which therapeutic efforts can be directed. Precisely, one of the central aims of VAGABOND is to identify new actionable cancer targets and develop treatments against these vulnerabilities.

Figure 2: Number of DNA mutations per megabase (Mb, 1 million base pairs) in pediatric (left) and adult (right) cancers. Source: Grobner et al., Nature (2018).

Pediatric cancers call for different treatments
Owing to their distinct characteristics, it would be reasonable to think that pediatric patients receive differentiated therapeutic options. However, for the most part, children have been addressed as “just small adults”. In fact, most drugs used to treat pediatric cancers were actually developed and approved for adult cancers, for which testing drugs in larger cohorts is less challenging (6). This strategy has taken the pediatric oncology treatment a long way in the past decades, with survival rates rising towards 80% on average (7). However, in multiple occasions adapting current therapies to treat children has proven rather unsuccessful due to differences in drug metabolization, interactions between the tumor and the immune system, or the molecular pathology of the tumors (8-10).

With less children dying of cancer today, the efforts have been expanded to minimizing the detrimental effects of treatments. While in adults long-term side effects are not a major concern, cured children are expected to live a long life after treatment. Standard therapies like chemotherapy and radiotherapy target growing tissues such as tumors, but also other organs that are in full growth during childhood. The unintentional damage to these areas can in some cases result in secondary tumors or organ-specific pathologies (learning impairments, vision defects, hearing loss, slowed growth… )(11). Efforts are being made to develop safer – while still efficacious – therapeutic strategies.

In summary, despite being closely related to adult tumors, pediatric cancers display distinct characteristics. Collaborative projects like VAGABOND offer the opportunity to study these tumors in depth as a separate entity. Moving forward, the involvement of larger cohorts of patients and the design of tailored studies will boost the development of efficacious and less toxic treatments for children with cancer.

If you want to know more, check out the various VAGABOND PhD project focusing on diverse pediatric cancer types here.

 

References

1. ECIS – European Cancer Information System. Cancer burden statistics and trends across Europe 2022 [Available from: https://ecis.jrc.ec.europa.eu].
2.  Ramsingh J, Casey H, Watson C. Adult neuroblastoma: a rare diagnosis of an adrenal mass. BMJ Case Rep. 2019;12(4).
3.  Zafar SN, Ahmad SQ, Zafar N. Retinoblastoma in an adult. BMC Res Notes. 2013;6:304.
4.  Grobner SN, Worst BC, Weischenfeldt J, Buchhalter I, Kleinheinz K, Rudneva VA, et al. The landscape of genomic alterations across childhood cancers. Nature. 2018;555(7696):321-7.
5.  Ma X, Liu Y, Liu Y, Alexandrov LB, Edmonson MN, Gawad C, et al. Pan-cancer genome and transcriptome analyses of 1,699 pediatric leukaemias and solid tumours. Nature. 2018;555(7696):371-6.
6.  Adamson PC, Houghton PJ, Perilongo G, Pritchard-Jones K. Drug discovery in pediatric oncology: roadblocks to progress. Nat Rev Clin Oncol. 2014;11(12):732-9.
7. Hudson MM, Link MP, Simone JV. Milestones in the curability of pediatric cancers. J Clin Oncol. 2014;32(23):2391-7.
8. Batchelor HK, Marriott JF. Pediatric pharmacokinetics: key considerations. Br J Clin Pharmacol. 2015;79(3):395-404.
9.  Mora J, Modak S. Nivolumab in pediatric cancer: children are not little adults. Lancet Oncol. 2020;21(4):474-6.
10. Carpenter EL, Mosse YP. Targeting ALK in neuroblastoma–preclinical and clinical advancements. Nat Rev Clin Oncol. 2012;9(7):391-9.
11. Erdmann F, Frederiksen LE, Bonaventure A, Mader L, Hasle H, Robison LL, et al. Childhood cancer: Survival, treatment modalities, late effects and improvements over time. Cancer Epidemiol. 2021;71(Pt B):101733.