Fig. 5. Precision+Therapy.

Collect as much data on the (epi)genetic make-up of the malignancy, its potential satellites and the patent. On the basis of somatic mutations, expression patterns, phosphorylation and levels of proteins as well as clinical knowledge devise a therapeutic intervention.Important questions that need answering: How much sampling is needed to get a comprehensive picture of the ecological niche and the various subclonal populations that make up the cancer? How best to identify the data that is of therapeutic relevance, tumours in adults can present >10,000 genetic alterations?⁹³ The centre piece of any precision therapy will be cell death-based treatment, to reduce tumour burden, combine this pharmacological molecules that target tumour-specific alterations, drugs that overcome apoptosis resistance such as BH3 mimetics (as discussed in Fig. 6) and substances that minimise cell proliferation (no full blockage as many therapeutic interventions are dependent on proliferation) and block invasion, as to avoid ‘the cost of migration’ or ‘go or grow’: it has been shown that the lack of oxygen can induce genes that are responsible for motility, which, in turn, reduces proliferation^73,74. Similarly, epithelial–to–mesenchymal transition which is most linked to invasion and several surface molecules, which also mediate adhesion should be prevented^10,94. In addition, add additional inhibitors to prevent the emergence of resistance mechanisms as discussed in Fig. 4b. The patient’s immune system should also be trained to further sponge up cells which have escaped the initial therapeutic intervention, here modern immunotherapy holds several promises³. Finally, known side effects can also be countered at this stage already. For example, neurocognitive impairment, i.e., cognitive dementia, associated with radiotherapy can be reduced by neurological and pharmacological interventions^95–97. Important questions that need answering: How predictable are the emerging resistance patterns, will blocking certain routes just provoke evolutionary escape via other mechanisms without greatly improving therapeutic outcome? Which sequence of administration should be chosen and how to further optimise this? The patients need to be closely monitored and any changes that suggest mutational escape of the tumour will need to fully restart the precision + therapeutic protocol. Even upon cure monitoring needs to be continued to identify long-term side effects, such as the emergence of secondary cancers, as early as possible. Important questions to ask: How to best monitor patients, as many radiation-based screening methods are themselves associated with increased cancer risks?⁴⁶ Which screening methods should be employed for cured patients, as the long-term side effects have proven to be hard to detect and will be extremely varied for a multi-modular therapy. Importantly, the free and frank exchange between the paediatric oncology community which was the basis for the successes of the 1970s must be sustained throughout every step