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Never Ending


Cancer's resistance to therapy is a fact of life, say researchers at the Moffitt Cancer Center. In a new opinion article in Nature Reviews Cancer, Moffitt researchers say cancer is subject to the same Darwinian processes of evolution and natural selection as any other organism, and that natural selection in the tumor microenvironment promotes the evolution of the tumor to resist any effort to kill it. "Cancer cell development, like any natural selection (or Darwinian) process, is governed by environmental selection forces and cellular adaptive strategies," says a Moffitt press release. "Investigating cancer and its proliferation through genetic changes and ignoring the adaptive landscape is most likely futile."

The authors add that tumors should be thought of as kinds of continents populated by different cellular species, that each have regional variations that have developed in response to different environmental conditions. "Nature selects for phenotype, not genotype, and population changes are dependent on local environmental selection forces," the authors write. "In cancers, evolution is fundamentally driven by environmental selection forces that interact with individual cellular strategies or phenotypes, which supervene cell genetics. Understanding cancer as a disease starts with identifying crucial environmental forces and corresponding adaptive cellular strategies." Resistance is "predictable" despite treatment with targeted therapies, says senior author Robert Gatenby in the press release.

"Even when there is a well-known target and a highly specific drug, increased survival is generally measured in months, not years," the authors add in the opinion piece. "Although there are some long-term survivors, for most advanced cancers and most patients, response to therapy is fleeting, owing to the inevitable evolution and proliferation of a resistant population."

But the same evolutionary processes can also be used to manage a patient's disease, the authors write. Because resistance can be anticipated, adaptive therapies can be developed to pre-empt resistance. Because cancer cells can only respond to current environmental forces, and can't anticipate future environmental conditions, therapies can be designed to direct the evolution in such a way as to prevent progression, keep resistance at bay for as long as possible, and improve outcome. The fight is more akin to chess than Whac-a-Mole, they add, and what is needed are "smart bombs" not "magic bullets."

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