Can oncology recapitulate paleontology? Lessons from species extinctions

Abstract

Although we can treat cancers with cytotoxic chemotherapies, target them with molecules that bind to oncogenic drivers, and induce substantial cell death with radiation, local and metastatic tumours recur, resulting in extensive morbidity and mortality. It is difficult to drive a tumour to extinction. Geographically dispersed species are perhaps equally resistant to extinction, but >99.9% of species that have ever existed have become extinct. By contrast, we are nowhere near that level of success in cancer therapy. The phenomena are broadly analogous. In both cases, a genetically diverse population mutates and evolves through natural selection. The goal of cancer therapy is to cause cancer cell population extinction or at least to limit any further increase in population size, so the tumour burden does not overwhelm the patient. However, despite available treatments, complete responses are rare, and partial responses are limited in duration. Many patients eventually relapse with tumours that evolve from cells that survive therapy. Similarly, species are remarkably resilient to environmental change. Paleontology can show us the conditions that lead to extinction and the characteristics of species that make them resistant to extinction. These lessons could be translated to improve cancer therapy and prognosis.

Tumor evolution: Linear, branching, neutral or punctuated?

“…The conceptual basis of this approach involves targeting the mechanisms that fuel evolution, rather than the end-product (ITH). Lessons from species extinction in paleontology may provide insight into treating tu-mors, since extinction is rarely caused by a single selective pressure, and geographic dispersion plays an important role in preventing extinction [137]. Thus targeting multiple selective pressures in combination may be needed to eradicate a tumor mass.…”

Resolution of Complex Issues in Genome Regulation and Cancer Requires Non-Linear and Network-Based Thermodynamics

“…This extreme endurance of tumour cells is likely borrowed from the phylogenetic evolution of cell response to stress [136,137], where the elastic epigenetic reprogramming was the main tool in the search of the available survival pathways. In this reprogramming, the protozoan, and even prokaryotic transcription cassettes (in the latter, first of all, of the DNA repair pathways), become dominating in the transcriptome of cancer gene network [138][139][140][141][142], particularly in association with polyploidy [143,144].…”

The role of spatial variations of abiotic factors in mediating intratumour phenotypic heterogeneity

“…oxygen and cytotoxic drug) diffuse in space, decay over time and are consumed by the cells. We note that the dynamics of abiotic factors is faster than cellular proliferation and death (Jacqueline et al, 2017;Walther et al, 2015). From a mathematical viewpoint, this means that we can assume oxygen and the cytotoxic drug to be in quasistationary equilibrium.…”