Cancer has been called malevolent. Devious. Even ingenious. It’s actually none of these. Cancer has no purpose or direction. As these wayward cells arise, they simply adapt to the environmental conditions of the tissues in which they exist. That concept, which springs from Charles Darwin’s theory of evolution, is guiding new approaches to fighting this common and deadly disease.
In Darwinian evolution, organisms that are well-adapted to their environments flourish and crowd out those that aren’t. My colleagues and I believe that much the same thing happens with cancer in a process we call adaptive oncogenesis.
A key component of this theory is that normal, healthy cells are best adapted to their normal, healthy environments. They have a competitive advantage over cells that develop cancer-causing mutations. In other words, environmental health and stability favors the status quo.
Just about everything we know that decreases the risk of developing cancer — exercise, healthful eating, not smoking, and the like — is associated with healthier tissues, which favor normal cell types.
Unfortunately, youthful, healthy tissues aren’t maintained forever. Aging and various behaviors or external insults, think cigarette smoking or radiation, modify tissues, and rarely for the better. Such changes favor cells with genetic changes that foster their ability to adapt to the altered environment. Damaged or degraded tissue favors undesirable (at least from our point of view) cell types — deviant cells that no longer play by the rules.
My lab has shown that the combination of changes in tissue environments and cells’ evolutionary responses to them can promote cancer.
This evolution-based theory doesn’t apply only to the origin of cancer. It is also relevant to treatment: Anti-cancer therapies that damage healthy tissues, like chemotherapy and radiation therapy, can promote the emergence of more aggressive cancer cells and even new types of cancer.
While many therapies are effective at inducing cancer remission, most advanced cancers return, sometimes within months. Cancers that relapse are even more refractory to treatment and more aggressive than they were initially. Adaptive oncogenesis attributes that in large part to the tissue damage induced by what is supposed to be a beneficial therapy. This creates conditions that favor the selection of cancer cells that are both resistant to the therapy and better adapted to the therapy-damaged environment.
It’s akin to a scenario that plays itself out in agriculture. When DDT and other powerful pesticides became available, farmers used them liberally. At first, they were highly effective. But over time, organisms with genes that conferred resistance to the pesticide began to thrive, rendering the compound less effective and prompting the use of a different one.
To get around this agricultural cat-and-mouse game, some farmers have turned to an approach known as integrated pest management. Instead of trying to vanquish a particular crop-damaging organism with overdoses of pesticide, it uses lesser amounts of it along with complementary strategies to reduce the economic impact of the pest to a set threshold. Combined with careful attention to keeping crops healthy, integrated pest management even helps sustain pests’ natural enemies. Using these tactics, farmers often get better results using less pesticide.
Thinking of cancer as a “pest,” Robert Gatenby and colleagues at the Moffitt Cancer Center in Florida have designed an approach to treating cancer that is similar to integrated pest management. They have developed treatment regimens to maintain chemotherapy-sensitive cancer cells which, during breaks from treatment, have an advantage over chemotherapy-resistant cancer cells. Their method, called adaptive therapy, involves treating the cancer to the point where the tumor burden is reduced, not eliminated. Reducing the intensity of treatment has four benefits: It is better tolerated by patients; it maintains healthy tissue as much as possible; it decreases the selective advantage for treatment-resistant clones; and it should better spare immune cells, which can serve as predators for cancer cells.
Adaptive therapy is now being tested in a clinical trial for prostate cancer. The early results are promising, with adaptive therapy leading to longer remissions than experienced by patients treated with the standard therapy.
Acceptance of this approach will require cancer physicians and researchers to abandon the “more is better” philosophy, whether for more treatment or more initial elimination of the cancer burden. With adaptive therapy, less can be more.
It is still early days for adaptive oncogenesis and adaptive therapy. We need to better understand the features of tissue environments that disfavor cancer genesis in youth and favor it in aged or damaged tissues. Discovering such factors will lead to new strategies for both preventing and treating cancer that make cancer cells the less-favored type by manipulating tissue environments. This research will also help develop therapies that target cancer cells with less collateral damage to normal cells and tissues, which some newer “targeted” therapies are beginning to do.
In the cancer ward, the instinct has long been to eliminate the enemy; success has typically been measured as the destruction of a cancer. But that doesn’t always yield a long-term solution, in good measure due to the failure to properly consider the impact of therapy on the whole body, which can be left heavily damaged. Controlling cancer requires thoughtful manipulation to direct cellular evolutionary trajectories, not brute force.
James DeGregori, Ph.D., is deputy director of the University of Colorado Cancer Center, professor of cancer biology in the Department of Biochemistry and Molecular Genetics at the University of Colorado School of Medicine, and author of “Adaptive Oncogenesis: A New Understanding of How Cancer Evolves Inside Us” (Harvard University Press, 2018). He has consulted for Tempus and is on the external advisory board of Mitotherapeutix.