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A nascent approach to cancer treatment is using lessons from Darwin’s theory of evolution.
Called adaptive therapy, the treatment stems from the recognition that cancerous cells, just like other forms of life, mutate and evolve in response to a changing environment. Traditional cancer treatment—continuously bombarding cancer cells with drugs—can encourage drug-resistant cells to multiply, eventually creating an untreatable tumor.
Adaptive therapy doesn’t try to eradicate the entire cancer. Instead, it seeks to reduce the treatable cells, stop treatment, and wait for those cells to grow back before treating them again. The presence of the treatable cells keeps the resistant cells at bay, as they compete against each other for resources. The idea, for now, is to keep the size of the tumor in check, and manage the cancer as a chronic condition.
The concept is still largely experimental, and experts caution that it needs more trials with larger groups of patients. A few doctors are starting to bring the idea into practice—primarily for late-stage, incurable cancers. But a growing number of researchers are paying attention and looking at cancer through an evolutionary, survival-of-the-fittest perspective.
“It really is a radically different way of approaching things,” said David Agus, a professor of medicine and engineering and founder of the University of Southern California’s Lawrence J. Ellison Institute for Transformative Medicine. “The idea is ready for real, randomized clinical trials in a big sense.”
Robert Gatenby, the co-founder of Florida-based Moffitt Cancer Center’s new Center of Excellence for Evolutionary Therapy, is a pioneer in the field and driving the bulk of the work in the U.S. on adaptive therapy. He is also a co-author on a small, pilot study, with initial results published in 2017 in Nature Communications, that showed that patients lasted at least 27 months on average without their tumors growing, compared with the usual 16.5 months, while receiving less of the same drug.
Dr. Gatenby, who had a background in physics before going into medicine, often points to pest control to describe therapy, and others in the field have picked up the analogy as well. In pest management, managers often don’t try to eliminate all of the insects but instead reduce their numbers, keeping the spray-sensitive bugs around to compete against the resistant bugs. Pest management developed the technique after overusing insecticides, which eliminated most of the insects. But some resistant bugs came crawling back.
“I think pest managers are about 30 years ahead of the oncologists,” said Carlo Maley, an evolutionary cancer biologist at Arizona State University and director of the new Arizona Cancer Evolution Center.
The field combining evolution and cancer, sometimes called evolutionary oncology, is decades old. But it has gained more clinical traction in recent years as mathematical modeling has better enabled researchers and mathematicians to predict how tumors will change in response to specific treatments.
“The field is small but it’s growing,” said Christine Iacobuzio-Donahue, director of the David M. Rubenstein Center for Pancreatic Cancer Research at Memorial Sloan Kettering Cancer Center, who researches cancer genetics. “Right now, people hear evolution and cancer and it’s intellectually stimulating, but we want to get past intellectually stimulating and save lives.”
The idea, however, isn’t always easy to sell, especially since cancer research and treatment has focused firmly on a cure for decades. The Moffitt pilot trial, which started in 2014 and was one of the first of its kind, had strict early stopping rules if it didn’t go well and took some convincing to get off the ground, Dr. Gatenby says.
And although the mathematical modeling predicted that the optimal time to halt treatment would be after the tumor had shrunk by 25%, the researchers decided to wait until the tumor had shrunk in half to make the concept more palatable, said Alexander Anderson, the chair of the Integrated Mathematical Oncology department at Moffitt, who works closely with Dr. Gatenby
The Moffitt pilot study originally enlisted 11 patients with late-stage, metastatic prostate cancer that was resistant to earlier treatments. The patients were put on the drug abiraterone, or Zytiga, and researchers tracked the tumors by monitoring a protein called PSA in their blood, as unusually high levels of the protein are linked to prostate cancer. Once the PSA levels dropped by half, the doctors halted all treatment until they rose again.
The treatment length was patient-specific: Some patients cycled through the treatment regimen every few months, while others took longer. At least one patient was able to go without the treatment for over a year. Patients, on average, lasted 27 months without tumor progression by the time the initial results were released. Dr. Gatenby says that the continued treatment has extended that average to 33 months, and the project expanded to 20 patients.
The patients also cumulatively reduced the use of the drug to roughly 40% of standard dosing, Dr. Gatenby says, meaning they spend less time dealing with side effects. One month of the drug can cost upward of $6,000, according to the paper, so a pause in treatment can also save a patient thousands of dollars.
“You need less drugs, less money,” said Toni Choueiri, the director of the Lank Center for Genitourinary Oncology at Dana-Farber Cancer Institute in Boston. “It’s a small study; there isn’t a comparative arm. But if this is true, the next thing is to take this to the next level.”
Alexander Anderson, left, and Robert Gatenby talk through ideas at the Moffitt Cancer Center. PHOTO: MOFFITT CANCER CENTER
Moffitt is currently expanding their work in applying adaptive therapy to treat prostate cancer, and the group is in the process of launching similar trials for melanoma, pediatric carcinoma, and thyroid and lung cancer. Dr. Maley and Athena Aktipis, an assistant professor of psychology at Arizona State University, are also working on opening an adaptive therapy trial for breast cancer after receiving a grant from the Arizona Department of Health Services.
“We don’t need to just look at killing tumor cells as the outcome,” said Dr. Aktipis, author of an upcoming book called “The Cheating Cell: How Evolution Helps Us Understand and Treat Cancer.” “We can look at the patient’s well being and making their lives as long and as high-quality as possible.”
Researchers aren’t sure, however, whether the technique will work with other cancers, especially those that don’t have as clear a marker as PSA. And sometimes, after the patients had been put on treatment, the drug didn’t work quite as well when the treatment restarted, said Jingsong Zhang, a genitourinary oncologist at Moffitt who treated the patients and was the first author on the pilot trial. Patients with shorter treatment cycles tended to respond better than those with longer ones.
“There are many questions,” said Dr. Gatenby. “The point isn’t that this should be broadly used. It’s the first evidence that we can use evolutionary principles to optimize therapy.”
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