New Center Takes Aim at Resistance

The Institute of Cancer Research (ICR) in London, UK, announced the launch of the Centre for Cancer Drug Discovery, which will bring together drug developers and evolutionary biologists to take on one of the biggest challenges in cancer treatment: drug resistance.

“We've made many strides in cancer treatment—we have targeted therapies, we have chemotherapeutics, we're really getting into immuno-oncology—but we know that resistance invariably happens, and then you get relapse,” explains Olivia Rossanese, PhD, head of biology in the new Centre for Cancer Drug Discovery. “In a number of cases, that resistance is essentially evolution and adaptation, and the evolution is driven by a Darwinian process.”

The center, which has secured more than $62 million in funding thus far, will house the ICR Centre for Evolution and Cancer and the Cancer Therapeutics Unit, together totaling about 280 researchers. “[It's] the physical manifestation of our ambition and our focus to really apply the principles of evolutionary biology and cancer biology, and combine that with our ability to design and develop drugs,” says Paul Workman, PhD, chief executive officer of the ICR.

Although the center won't open until April 2020, scientists from both groups are already collaborating to determine the most effective combinations of existing cancer therapies, based on how tumors evolve, and developing drugs to target the evolution of cancer.

One approach for the drug combination studies is evolutionary herding, wherein researchers apply knowledge of how cancer cells evolve in response to different therapies to try to control the cancer's behavior. The idea, Rossanese says, is to thoughtfully sequence drugs and administer combinations “to herd cancer cells through various evolutionary pathways until, eventually, we create a situation that the cancer cells can't adapt to or escape from.” This research will involve genomic sequencing to track how cancer cells are evolving over time, as well as artificial intelligence and modeling approaches that predict the trajectory of this evolution, Workman adds.

In addition, rather than stopping the growth of cancer cells, researchers want to develop therapies that halt a cancer's evolution, thus preventing resistance. Ongoing work centers on APOBEC3B, a cytosine deaminase that can mutate DNA. Cancer cells often overexpress APOBEC3B—in fact, the enzyme's mutational signature has been observed in more than half of human cancers—and studies have shown that this overexpression can drive resistance by increasing genomic diversity. Thus, researchers are identifying and developing APOBEC3B inhibitors. “You're not really making a drug against an oncogene target, you're making a drug that you would use alongside other medicines to prevent that adaptation and that evolution, and delay time to resistance,” Rossanese says.

Rossanese and Workman hope that these and other projects will lead to treatment strategies that prolong patient responses. “We don't just want to be the team that simply comes up with the next kinase inhibitor or the next MDR modulator, and then sits back and waits for the resistance to develop,” Workman says. “Cancer drug resistance is an arms race, and we want to stay ahead of the cancer cells.” –Catherine Caruso

For more news on cancer research, visit Cancer Discovery online at http://cancerdiscovery.aacrjournals.org/CDNews.