Challenging Somatic Mutation Theory in Cancer – Viewing Tumours as Complex Adaptive System

Novel approaches to cure childhood cancer is urgently needed. Viewing tumour as complex adaptive system with inherent laws of growth will help develop better and more efficient therapy.

Currently, the paradigm in cancer research is applying genomic and transcriptomic data to cohorts of patients, searching for distinctive genetic biomarkers that can be targetable by developing drugs in quest for precision medicine efforts. Despite these ongoing, large initiatives in paediatric cancer, few actionable somatic mutations have been found. Overall, the genetic landscape of childhood cancer is relatively silent with some notable exceprtions like mutations in Alk gene or Ntrk1/2/3-fusions that have improved cure for rare tumours like neuroblastoma and soft-tissue sarcoma.

However, as we are learning from tumour biology, tumours evolve and adapt to its environment, including developing resistance mechanism to for example tyrosiner receptor kinase inhibitors.

Another approach is to view cancer as a complex adaptive system, where a system is characterised to be more complex than the sum of individual parts. Groups of genes and their resulting proteins interact to produce a specific action, ie growth or proliferation. Further, complex adaptive system is characterise by three major properties: 1) independent parts that are interconnected and interactive; 2) they must be capable of forming and changing strategies. This could be exemplified by switching from oxidative phosphorylation to aerobic glycolysis in tumour metabolism; 3) they alter the strength of their interaction with others in a way that maximises the average fitness of the system.

In this theory, it holds true that a minor event can lead to a catastrophic event, such as uncontrolled cell division leading to tumour formation.

By applying the theory of complex adaptive system in oncology, potential new strategies for therapy may be revealed. Currently, chemotherapy succeds in eradicating some clones in the tumour, but in case of metastatic and slowly dividing tumour cells, this leads to tumour recurrence and death. Alternatively, adoptive treatment has been developed where a chemosensitive clone is suppressed but not eradicated, but indirectly keeping other clones with slower proliferation in check. In prostate cancer, this approach have been shown to prolong survival in chemo- and immune therapy resistant cancer but this concept hasn’t been developed for childhood cancer. To reach the goal of controlling and curing cancer, novel approaches is needed, and cross-diciplinary approach is needed between mathematics to understand and quantify cancer as complex adaptive system and other medical specialities to understand underlying biology as well as devising new chemotherapy strategies.

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