Is adaptive therapy natural?

Abstract

Research suggests that progression-free survival can be prolonged by integrating evolutionary principles into clinical cancer treatment protocols. The goal is to prevent or slow the proliferation of resistant malignant cell populations. The logic behind this therapy relies on ecological and evolutionary processes. These same processes would be available to natural selection in decreasing the probability of an organism’s death due to cancer. We propose that organisms’ anticancer adaptions include not only ones for preventing cancer but also ones for directing and retarding the evolution of life-threatening cancer cells. We term this last strategy natural adaptive therapy (NAT). The body’s NAT might include a lower than otherwise possible immune response. A restrained immune response might forego maximum short-term kill rates. Restraint would forestall immune-resistant cancer cells and produce long-term durable control of the cancer population. Here, we define, develop, and explore the possibility of NAT. The discovery of NAT mechanisms could identify new strategies in tumor prevention and treatments. Furthermore, we discuss the potential risks of immunotherapies that force the immune system to ramp up the short-term kill rates of malignant cancer cells in a manner that undermines the body’s NAT and accelerates the evolution of immune resistance.

Can postfertile life stages evolve as an anticancer mechanism?

“…For instance, fluctuating levels of circulating estrogen and progesterone during the menstrual cycle are known to increase breast cancer susceptibility in women (e.g., estrogen receptor and breast cancer [62,63], see also [64] for a recent review, but see also [65,66]). Menopause (i.e., the cessation of menstrual bleeding following a 12-month period of amenorrhea [67,68]) typically occurs between 45 and 55 years of age in women [69] and may have thus evolved as a “natural hormonal therapy” to stop, or limit, the growth of such kind of malignancies before a fatal threshold is reached (see also [70]).…”

Hepatocellular carcinomas: evolution to sorafenib resistance through hepatic leukaemia factor

“…From the perspective of Darwinian evolution, tumour progression results from the competition of diverse cancer cell clones for the cancer cell niche. Aggressive anticancer therapies sweep away proliferating cells, thereby releasing the competitive pressure from quiescent cancer stem cells endowed with detoxification, survival and metabolic fitness 11. The work by Xiang et al suggests that anticancer therapy should combine conventional antiproliferative and tumour mass-reducing approaches (including biotherapy and immunotherapy), with strategies to prevent the development of cancer stem cell contingents by attacking their specific attributes, such as metabolic reprogramming8 or the development of pluripotency features (figure 1B).…”

Exploiting evolutionary trade-offs to combat antibiotic resistance

“…The therapeutic use of drugs against microbial pathogens and cancer is currently undergoing a paradigm shift from traditional therapies toward adaptive therapies, in which disease is treated as an evolutionary process to minimize the risk of drug resistance evolution [1][2][3][4][5] .…”

“…In contrast, adaptive therapies aim to manage the disease without necessarily eradicating it. Evidence from studies of adaptive therapies suggest that -rather than forcing pathogenic cells into evolving elaborate forms of drug resistance during the long-term administration of antimicrobial or anti-cancer drugs -pathogens should be treated using repeated, short-term bouts of drug application that are interrupted by periods without treatment 3,5 . The rationale for this approach is that, during these periods without treatment, resistant cells will be naturally outcompeted by non-resistant cells (or cells with lower levels of resistance) either due to genetic drifts or because the resistant cells are frequently less fit than non-resistant cells in the absence of drug 1,2 .…”

“…Multiple studies have shown that integrating this evolutionary principle into clinical treatment protocols can drastically improve disease progression in patients suffering from advanced forms of infectious disease or cancer 1,[3][4][5][6] . For instance, adopting this approach dramatically improved the effectiveness of abiraterone-mediated treatment of metastatic forms of prostate cancer, where just one patient out of 11 developed therapeutic resistance during a course of adaptive therapy, compared with 14 out of 16 patients who developed therapeutic resistance following traditional therapy 5 .…”