Can oncology recapitulate paleontology? Lessons from species extinctions

Abstract

Although we can treat cancers with cytotoxic chemotherapies, target them with molecules that inhibit oncogenic drivers, and induce substantial cell death with radiation, local and metastatic tumours recur, resulting in extensive morbidity and mortality. Indeed, driving a tumour to extinction is difficult. Geographically dispersed species of organisms are perhaps equally resistant to extinction, but >99.9% of species that have ever existed on this planet 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, to prevent the tumour burden from overwhelming 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.

Figure 1. Causes of species extinction

Known causes of mass extinctions and background extinctions are shown. Five historical mass extinctions are demonstrated by paleontological evidence, and a sixth is currently occurring.

Figure 2. Potential cancer therapies inspired by mechanisms of extinction

Lessons from paleontology have taught us that one selective pressure is not enough to successfully attack cancer, but rather that multiple selective pressures are necessary, targeting the tumour from different directions. The multiple pressures could target the different microenvironments in a spatially heterogeneous tumour. Further paleontology also suggests that we should apply combinations of chemotherapy, adaptive therapy, anti-angiogenic therapy, hyperthermia, bacteriolytic therapy, and targeted therapy over long periods, without breaks, to maintain selective pressures on the neoplastic cells, as it is done with metronomic therapies.