Abstract
Advanced metastatic cancer is currently not curable and the major barrier to eliminating the disease in patients is the resistance of subpopulations of tumor cells to drug treatments. These resistant subpopulations can arise stochastically among the billions of tumor cells in a patient or emerge over time during therapy due to adaptive mechanisms and the selective pressures of drug therapies. Epigenetic mechanisms play important roles in tumor cell diversity and adaptability, and are regulated by metabolic pathways. Here, I discuss knowledge from ecology, evolution, infectious disease, species extinction, metabolism and epigenetics to synthesize a roadmap to a clinically feasible approach to help homogenize tumor cells and, in combination with drug treatments, drive their extinction. Specifically, cycles of starvation and hyperthermia could help synchronize tumor cells and constrain epigenetic diversity and adaptability by limiting substrates and impairing the activity of chromatin modifying enzymes. Hyperthermia could also help prevent cancer cells from entering dangerous hibernation-like states. I propose steps to a treatment paradigm to help drive cancer extinction that builds on the successes of fasting, hyperthermia and immunotherapy and is achievable in patients. Finally, I highlight the many unknowns, opportunities for discovery and that stochastic gene and allele level epigenetic mechanisms pose a major barrier to cancer extinction that warrants deeper investigation.
Highlights
Cancer is a disease that results from fundamental biological processes and mechanisms that enable diversity, adaptation and evolution (Merlo et al, 2006; Maley et al, 2017; McGranahan and Swanton, 2017)
Reducing and increasing the ambient temperature can synchronize dividing cells in culture (Rieder and Cole, 2002; Bánfalvi, 2017). This suggests that cycles of starvation, re-feeding and increased temperature could be combined in patients and timed with chemotherapy treatments to help reduce cellular diversity by synchronizing tumor cell populations for maximum killing during a chemotherapy treatment strike (Figure 8)
We need an understanding of the short-term and long-term epigenetic mechanisms involved, their regulation by different metabolic mechanisms and their roles in the initiation and persistence of cancer and the evolution of drug resistance
Summary
Cancer is a disease that results from fundamental biological processes and mechanisms that enable diversity, adaptation and evolution (Merlo et al, 2006; Maley et al, 2017; McGranahan and Swanton, 2017). No study has yet determined whether starvation reduces stochastic epigenetic dynamics within a cell over time, epigenetic diversity across populations of cells, or capabilities for epigenetic and gene expression adaptability in response to new and additional stressors (e.g., chemotherapy strikes).
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