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Home https://server7.kproxy.com/servlet/redirect.srv/sruj/smyrwpoii/p2/ Health https://server7.kproxy.com/servlet/redirect.srv/sruj/smyrwpoii/p2/ A Clever New Strategy for Treating Cancer, Thanks to Darwin

A Clever New Strategy for Treating Cancer, Thanks to Darwin

In October 1854, and a government entomologist was inspecting some farmland outside the city of Ottawa, in northern Illinois, when he came upon a disturbing scene in a cabbage patch. the vegetables were "literally riddled with holes, more than half their substance being eaten away." With each step he took around the devastated cabbages, tiny rocks of little ash-gray moths rose from the ground and fluttered away. This was, it appears, the first record in the United States of the diamondback moth, an invasive pest that in its larval form shows a fondness for cruciferous vegetables. By the late 1

800s the moths were chewing through the leaves of the cabbages, brussels sprouts, collards, and kale from Florida to Colorado

To fight this invasion, farmers began bombarding their fields with primitive pesticides. This worked. Or seemed to. It killed most of the moths, but those who survived the poison replicated, and the population bounced back stronger than ever. For decades, one pesticide after another failed as the moths evolved to resist it. Even the grievously toxic DDT was no match for the diamondback. Beginning in the late 1950s, agricultural experts began to abandon the idea of ​​eradication and adopted a new strategy. Farmers would leave the moth alone until their numbers exceeded certain thresholds, and only then would they deploy pesticides. Remarkably, this helped.

When Robert Gatenby heard this history of the diamondback moth in 2008, he immediately latched onto it. Gatenby is not a farmer nor an agronomist nor a fan of cruciferous vegetables-in fact, he deeply loathes brussels sprouts. He is a radiologist by training and head of the radiology department at the H. Lee Moffitt Cancer Center in Tampa, Florida. But unlike your typical doctor, he is also obsessed with the evolutionary principles put forth by Charles Darwin more than 150 years ago.

Like the diamondback moth, cancer cells develop resistance to the powerful chemicals deployed to destroy them. Even if cancer therapies kill most of the cells they target, a small subset can survive, largely thanks to genetic changes that render them resistant. In advanced-stage cancer, it's generally a matter of when, if not, the pugnacious surviving cells become an unstoppable force. Gatenby thought this deadly outcome could be prevented. His idea was to expose a tumor to medication intermittently, rather than a constant assault, thus reducing the pressure on his cells to evolve resistance.

Just as environmentalists allow for a manageable population of diamondback moths to exist, Gatenby's method would allow cancer remains in the body as long as it does not spread further. To test this idea, Gatenby got permission in 2014 to run a trial on advanced-stage prostate cancer patients at Moffitt. The patients had cancer that no longer responded to treatment; their drug-resistant cells were winning an evolutionary battle within the body, surviving an onslaught of toxic drugs where weaker cancerous cells had succumbed. It was hoped that by using a precise drug-dosing scheme developed using evolutionary principles, they could slow the growth of the mutations that would endow some cancer cells with fitness to survive.

One of the patients in the trial was Robert Butler, a British oil-exploration engineer who had retired in Tampa. In 2007 he was diagnosed with prostate cancer, and seven years later, after taking the drug Lupron and getting blasts of radiation, his prostate tumor had progressed to stage 4, advanced cancer. Butler did not give up, though. He tried a newly-approved immunotherapy treatment-one that involved cells from his blood sent by courier to a facility outside Atlanta, where they were mixed with a molecule that activates immune cells, and then shipped back to Florida to be injected back into him. (19659003) When Butler and his wife showed up at his oncologist's office at the Moffitt Cancer Center in August 2014, they were braced for what would come next; they had heard about invasive treatments like radioactive seed implants. So they were intrigued when the doctor told them about Gatenby's trial and asked if Butler wanted to participate. He would take a powerful and extremely expensive drug called Zytiga, but not in the scorched-earth, kill-all-the-cells fashion that is standard. Instead, he would only receive as much Zytiga as was necessary to stop the cancer from growing. The idea was radical and counterintuitive. His last best shot at escaping death from his cancer was to give up on curing him.

Knowing the modified Zytiga regimen was not designed to rid him of cancer left Butler, the engineer, with a question about how doctors would measure the success of their new treatment approach. He asked, "How do we know this stuff is working?" And one of his doctors replied, "Well, you will not be dead."

In the United States we use military metaphors when we talk about cancer. We fight and we fight, and if we survive, we're victorious. The attitude traces back to part in 1969, when the Citizens Committee for the Conquest of Cancer ran an ad in The Washington Post and The New York Times imploring the president with the words "Mr . Nixon: You can cure cancer. "The call to action helped trigger the country's" war on cancer "with a determination that, using enough medical weaponry, the malignant foe could be obliterated

By mid-1970s, however, signs were beginning to emerge that certain strategies aimed at total eradication were liable to backfire. Against this background, a cancer researcher named Peter Nowell published a seminal paper in Science in 1976. Nowell conjectured that evolutionary forces drive certain cell populations in tumors to become progressively more malignant over time. The cells inside a tumor are in competition, not only with nearby healthy cells, Nowell argues, but also with each other. Nowell suggested – and later research confirmed – that certain DNA alterations grant cancer cells resistance against chemotherapy or other treatments, causing them to edge out drug-sensitive cells through a process of natural selection

Nowell conveyed his ideas to his students at University of Pennsylvania School of Medicine, sometimes smoking and cigarette as he lectured. His theories were respected but slow to catch on. He stressed that tumors may become more deadly as they accumulate more genetic errors. It was an idea ahead of its time. Scientists back then did not have the technical ability to measure all the changes in the vast genomes of tumor cells. Instead, they could only track the tidbits of DNA at a time, and most scientists saw cancer as the fruit of just a few genetic mutations

One of the medical students listening to Nowell's lecture in the late 1970s happened to be a young Bob Gatenby. But Nowell's ideas did not make a strong impression on him, Gatenby says; Instead, what inspired him was what he had witnessed in his first years as a practicing radiologist on the bloody front lines of the war on cancer

"I could not understand why you would treat someone with a fatal disease and kill them with your therapy. It did not feel right to me. "

By mid-1980s, Gatenby had secured a job at the Fox Chase Cancer Center in Philadelphia. At that hospital and others around the country, clinical trials have put breast cancer patients through an extreme treatment: a combination of a potentially lethal dose of chemotherapy followed by a bone marrow transplant. The treatment was harrowing. The women had diarrhea and nausea, and some had so much lung damage they had difficulty breathing. Others experienced liver damage and weakened immune systems that left them vulnerable to serious infections. As a radiologist, Gatenby's job was to interpret x-rays and other scans of the patients, and he saw the treatment failing. Out of over 30,000 women with breast cancer in the US who underwent the procedure between 1985 and 1998, as many as 15 percent died of the treatment itself. "What happened was these women suffered horribly, and they were not cured," Gatenby says.

Around the same time as breast cancer trials, the father of a colleague of Gatenby's came to the hospital to receive an initial, aggressive round of chemotherapy for lung cancer. According to her colleague, her father arrived on a Friday with no apparent symptoms and was dead by Monday. "That event was very traumatic," Gatenby recalls, and the cause to him seemed obvious. "I could not understand why you would treat someone with a fatal disease and kill them with your treatment. Gatenby's own father died of esophageal cancer.

Gatenby felt there should be a better way to treat cancer-to outsmart it rather than carpet-bomb it. He had studied physics in college and believed that biologists could leverage equations to capture forces driving cancer the same way physicists use math to describe phenomena like gravity. While he had put forth general theories about how cancers followed evolutionary principles, Gatenby was taking a leap: He wanted to figure out how to describe the evolution of cancers with mathematical formulas

Robert Gatenby, a radiologist, saw patients suffer from intensive breast cancer treatments. (19659019) Mark Sommerfeld

By 1989, Bob Gatenby was preoccupied with the modeling of the evolution of cancers. During the day he would scrutinize the x-rays of cancer patients, and at night, after he and his wife had put their young kids to bed, he would sit at the kitchen table in their suburban Philadelphia home and pore over medical journals. (19659003) Gatenby recalled that the ecologists had come up to the question of whether or not the cancer cells were out of the body, with equations to describe the balance between predators and prey. As an undergraduate at Princeton University, he had learned the classic example of the math that plotted how the growing populations of snowshoe hares fuel the rise of the lynx that feeds them. He began dusting off old books and buying new ones to educate himself on species interactions

For a year Gatenby read and mulled. Then, in 1990, on a family trip to the Atlantic coast of Georgia, he found himself stuck in a hotel room one afternoon with his two napping children. Out of nowhere, an idea presented itself. He grabbed a pad of hotel paper and pen and began scribling down some of the key formulas from population ecology. These formulas, called Lotka-Volterra equations, have been used since the 1920s to model predator-prey interactions and, later, competition dynamics between species, and were among those he had recently brushed up at home. Gatenby thought this set of formulas could also describe how tumor cells compete with healthy cells for energy resources such as the glucose that fuels them

When he returned to Philadelphia, he spent what time he could at a typewriter composing a paper that laid out this theoretical model. As soon as he finished, he showed it to some colleagues. He thought it was ridiculous to try to use ecological equations to model cancer. "They say that they hated it would not do justice to how negative they were about it," he says. His peers thought that a brief set of formulas could not capture cancer's seemingly infinite complexities.

Louis Weiner, who worked alongside Gatenby at the time, recalls that their colleagues viewed Gatenby's ideas as offbeat. "Treatment orthodoxy at that time favored high-intensity, dose-dense treatments aiming to eradicate every last tumor cell in a cancer patient," says Weiner, who is now director of the Georgetown Lombardi Comprehensive Cancer Center in Washington, DC. "


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But Gatenby pressed on and succeeded in getting the paper, chock-full of Lotka- Volterra equations, accepted in the prominent journal Cancer Research in 1991.

Despite the publication of his theory, he still could not convince oncologists that his idea had practical merit. "I think they felt intimidated," Gatenby says. "In the years afterward, Gatenby moved up the ladder to lead the Department of Diagnostic Imaging at Fox Chase Cancer"

In the years afterward, Gatenby moved up the ladder to lead the Department of Diagnostic Imaging at Fox Chase Cancer Center. He was later appointed head of the department of radiology at the University of Arizona College of Medicine in Tucson, and he continued to gain recognition for his skilled interpretation of scans and to receive federal grants to study cancer

Then, in 2007, the Moffitt Cancer Center offered Gatenby and a job as chair of the radiology department. He had a condition: He would come if the hospital created a division where he could seriously pursue the link between Darwin's principles and cancer. The Integrated Mathematical Oncology Department, born from this negotiation, is the first math department in a cancer hospital, he says. Finally, Gatenby had a place where he could put his ideas to the test.

Gatenby arrives at his corner office at Moffitt most days by 7 am. He's 67 now, and his hair is gray at the temple, but his eyebrows are still brown. His children – those who were sleeping in that hotel room when he jotted down his Darwinian inspiration – now have children of their own, and he has the "I ♥ Grandpa" coffee mug to prove it. A hospital lanyard around his neck, he rolled up his crisp shirtsleeves and settled down at his desk. Outside his office, roughly 30 scientists and PhD students spend their days researching patterns of cancer growth using equations like those describing population dynamics.

To Gatenby's knowledge, none had endeavored to exploit evolution against cancer in a clinical trial until he developed his prostate cancer experiment. He has picked prostate cancer to test this approach partly because, unlike other cancers, a routine blood draw for a molecule called prostate-specific antigen (PSA) can offer an immediate proxy for cancer progression

To design a clinical trial, Gatenby and his Moffitt collaborators first needed to account for their idea that tumor cells are living against each other for resources. They turned to game theory to plot this dynamic and plugged the numbers into the Lotka-Volterra equations. In the simulations, the typical administration of the Zytiga syndrome in patients with advanced prostate cancer in patients with advanced prostate cancer, drug led to drug-resistant cancer cells rapidly running rampant. The treatment would eventually fail every time. That bleak outcome matched with the results seen in hospital records. In contrast, the computer simulations suggested that if Zytiga were administered only when the tumor seemed to be growing, then the drug-resistant cells would take much longer to gain enough benefit to overcome the cancer

In 2014 the Moffitt team managed to Take the first small study to test this adaptive therapy approach off the ground, recruiting Robert Butler and a small group of other men with advanced prostate cancer. Butler's oncologist explained to him how it would work. He would stay on the Lupron he had taken for years, and every month he would go to the hospital to get his PSA level tested, to judge whether his prostate tumor was growing. Every three months, he would get a CT scan and a full-body bone scan to watch for spread spread. Whenever his PSA level edged above where he stood when he entered the trial, he would start taking the more powerful Zytiga. But when his PSA level dropped to half the baseline, he could go without Zytiga. This is appealing because Zytiga and drugs like it can cause side effects such as hot flashes, muscle pain, and hypertension

The Moffitt approach also promised to be far cheaper than taking Zytiga continuously. When purchased wholesale, and one-month supply costs almost $ 11,000. Butler had health insurance, but even so, his first month's supply each year would put him back $ 2,700 in out-of-pocket copayments, and $ 400 a month thereafter. Going off the drug whenever his PSA level was low would translate to huge cost savings.

"Conceptually it's a beautifully simple approach. He is turning cancer into a chronic disease. "

Butler was involved in a so-called pilot trial, which was less rigorous than a large clinical trial because he did not randomly assign patients to receive the experimental or standard treatments. Rather, the study relied on a group of patients treated outside of the trial as well as results from a 2013 paper on Zytiga to come up with a benchmark for how patients typically get fared when receiving continuous dosing of the drug

of their new trial trickled in, the Moffitt scientists were gratified and relieved. Before the trial, "we were, to be honest, terrified," Gatenby says. The benefit of adaptive therapy seems to be huge. Of the 11 men in the study, one left the trial after his disease spread, but most were living longer than expected without their cancer progressing. Men getting continuous dosing of Zytiga go to a median of 16.5 months before the cancer becomes resistant to the drug and spreads. In comparison, the median time to progression for men receiving adaptive therapy was at least 27 months. Moreover, they were on average less than half of the standard amount of Zytiga. Joel Brown, an evolutionary ecologist and one of Gatenby's collaborators, said the team felt a moral obligation to get the word out: "The effect was so great that it would be unethical not to report it immediately."

They published and reported in 2017, far earlier than anticipated, a generally positive reaction from prostate experts-especially because it suggested that people with cancer might live longer with less medication. "I think that's fantastic," says Peter Nelson, an oncologist who studies prostate cancer at the Fred Hutchinson Cancer Research Center in Seattle. Jason Somarelli, a biologist at the Duke Cancer Institute, calls Gatenby and a pioneer: "He's turning cancer into a chronic disease."

Butler, who is 75, has gone for long periods off Zytiga-with stretches lasting as long as five months. "I'm now the poster boy, they say," says Butler. He is one of the best responders in the study.

Some doctors are already trying adaptive therapy on patients outside of clinical trials. In 2017, a doctor in Oregon, inspired by Gatenby's pilot study, started a prostate cancer patient on a modified version of the approach when he refused the standard continuous dosing. She has since started treating a second man using adaptive therapy. Other oncologists might be doing the same. It's almost impossible to know for sure, because adaptive therapy does not require government approval. The protocol uses already-approved medications, and the US Food and Drug Administration does not prescribe specific dosage schedules.

Experts urge caution, however. The prostate cancer study was very small, and without a randomly assigned control group the results are not truly reliable. While most of the men in the trial remained stable, four more saw their cancer progress since the paper came out. "This is an approach that needs to be carefully studied in prospective clinical trials before it is adopted into clinical practice," said Richard L. Schilsky, chief medical officer for the American Society of Clinical Oncology. Years could pass before a large-scale test of adaptive therapy takes place. Only Lichtenfeld, interim chief medical officer of the American Cancer Society, echoes Schilsky's concerns. "Is it intriguing? Yes, "says Lichtenfeld. "There is still a long way to go."

Gatenby agrees that adaptive therapy needs rigorous testing. He conveys a kind of humility you do not see very often in the upper reaches of medical science. He told me several times that he is not an interesting subject to write about, and more than once I heard close colleagues mangle the pronunciation of his name (which is pronounced GATE-en-bee); apparently he had never corrected them. But when he believes in something, he does not relent. And he believes in adaptive therapy. "He's like a teddy bear, but underneath that soft exterior he's made of steel," says Athena Aktipis, who studies teoretical and cancer biology at Arizona State University and has collaborated with Gatenby.

Late last year, Gatenby presented his work at and a meeting of prostate cancer specialists. In the question and answer session afterward, the attendee shared his surprise at the results. "I guess what you're saying is that we've been doing it wrong all these years," the man mused, according to Gatenby. "I was literally speechless for a few moments," Gatenby admits, "and then I said," Well, yeah, I guess that's what I'm saying. "" He is still living on the exchange and wishes he could somehow find the man and apologize. He's not taking back what he said; he does not think the profession can do better. But, he says, "I should have been more diplomatic."

In 2016, and couple dozen researchers gathered in a conference room at an ultramodern genetic sequencing center along the banks of the River Cam, 9 miles outside of Cambridge, England. The gathering brought together experts to discuss how principles of ecology might apply to cancer. When they took a break, their idea of ​​fun was to play a round of "Game of Clones," in which a small group of scientists pretended to be cancer cells trying to persuade the maximum number of other researchers bouncing around the room to be their malignant clones

During this meeting, one overarching theme kept popping up: Evolution does not work the same way in all cancers. It is not even clear that Darwinian natural selection always determines the genetic mutations that abound within a tumor. A study of colon cancer samples conducted by one of the conference attendees, Andrea Sottoriva of the Institute of Cancer Research in London, and Christina Curtis, a computational biologist at Stanford University, suggested a different pattern

When colorectal tumors begin to form , there seems to be a "big bang" of mutations. This initial explosion of cellular diversity in these colon cancers is followed by a period in which random genetic changes occur and become more prevalent than purely occurrence rather than because mutations confer some sort of competitive advantage. It is still unclear whether adaptive therapy, which operates on the assumption that there is a Darwinian competition between tumor cells, would work well for cancers where the mutations arise continuously by chance

Still, a kind of consensus emerged, and a year after the Cambridge meeting, the organizers published a statement outlining how cancers could be better classified. Twenty-two researchers-some of the greatest names in the field of evolutionary oncology, including Gatenby-coauthored the document.

One important factor in the group's proposed classification scheme is a measure of how swiftly a cancer is mutating. In the past decade, faster DNA sequencing tools have shown that Nowell-Gatenby's old professor, the cigarette-smoking pioneer in applying evolutionary thinking to cancer-was prescient: Individual tumors often bristle with rapid-fire genetic changes. Rather than two or three initial errors, a set of uncontrolled growth chains, many tumors are the result of several series of mutations. A significant experiment published in 2012 found at least 128 different DNA mutations in various kidney tumor samples from one patient, for example. There is some evidence that more mutations there are, the more aggressive and cancer tends to be, suggesting a higher chance that one of these DNA changes will confer tumor cells with the potential to be drug-resistant. Given the technological advances, it is not too far-fetched to think that within the coming decade, doctors will routinely measure the amount of mutations in their patients' tumors

Today most cancers are assessed using a system that dates back to the 1940s. Doctors typically evaluate factors such as whether a cancer has spread to lymph nodes or beyond and on the basis of these attributes determine its "stage." On one end of the spectrum are stage 1 cancers, which are relatively restricted, while at the other end has stage 4 cancers, which have spread extensively.

The proposed categorization system that grew out of the Cambridge meeting would look at cancer in a completely new way. Rather than four stages of cancer, the authors of the 2017 consensus statement suggest no less than 16 different categories – for example, tumors that have a slow cell turnover and a low rate of accumulating mutations, or tumors that are a hotbed of genetic diversity with fast replicating cells competing for resources. This latter type of tumor may be the most likely to evolve a way to outcompete drug-sensitive cells in the body and thus, in some cases, be the most dangerous. A fast-moving cancer of this kind might also be the best candidate for adaptive therapy.

Around the time the consensus statement came out, Gatenby and his collaborators in Tampa were hard at work running cell experiments in a lab down the hall from his office. The goal was to prove a key tenet of adaptive therapy. Gatenby's approach assumes that when drug treatment is removed, drug-resistant cancer cells will replicate more slowly than drug-sensitive cells. The theory rests on the assumption that those resilient cells need lots of energy to maintain their armor against the medication meant to kill them. During treatment breaks, the thinking goes, the fuel-hungry resistant cells are outcompeted by drug-sensitive cells, which need fewer resources to thrive.

To gather evidence for this idea, Gatenby's research team has placed human breast cancer cells with resistance to the drug doxorubicin in a petri dish alongside an equal-sized population of doxorubicin-sensitive breast cancer cells and watched the two groups fight for resources. By day 10 the resistant cells made only 20 percent of the cells in the dish and continued to slowly decline from there. At the end of the experiment, published last year, these resistant cells had dropped to around 10 percent of the total population.

Granted, this experiment happened in a petri dish, not a human body, or even the body of a lab rat. Some leading cancer specialists agree with Gatenby that drug-resistant cells are likely outcompeted by other cells when cancer medication is withdrawn. But, say other, what if Gatenby is wrong? What if resistant cells actually thrive during the period when the patient is taken off drugs? The risks are high.

Rethinking cancer as and chronic illness requires a mental shift-shift that other changes in cancer therapy may be easing. There is a practice of letting cancer patients take doctor-supervised "drug holidays" from their medications, for example. And we've adapted our thinking when it comes to medicine before. Doctors once thought that stress was the primary culprit behind ulcers, but biologists uncovered a bacterium as the main cause. More recently we've gotten used to the weird idea that trillions of bacteria live in our gut microbiome

Perhaps, then, it's not a huge stretch to think we might tolerate coexisting with cancer cells as long as we can prevent they from growing unchecked. Although Darwin put forth ideas about what has become known as macroevolution-the rise and fall of the species, whether beetles or bald eagles – this new view of cancer could be an example of what we might call "endo-evolution": natural selection

The American Cancer Society recognizes that some cancers are already managed as chronic illnesses. In some cases, doctors simply try to keep malignancies from spreading with new rounds of medication. Gatenby's adaptive therapy aims to take the guesswork out of the treatment. More trials at Moffitt are in the planning stages or underway for cancers affecting the breast, skin and thyroid, in addition to a new, larger trial in prostate cancer patients. Across the country, in Arizona, Athena Aktipis and her husband and scientific collaborator, Carlo Maley, have secured a grant to begin a breast cancer trial using adaptive therapy in conjunction with a local branch of the Mayo Clinic

It is not and a huge stretch to think we might tolerate coexisting with cancer cells as long as we can prevent them from growing unchecked

But the idea of ​​cancer as an implacable enemy that needs to be annihilated runs deep. Even Gatenby feels it, especially when it comes to children. When his daughter was a teenager, one of her classmates died of a form of cancer called rhabdomyosarcoma. He never met his daughter’s friend but heard about his decline. Then, last year, a pediatric oncologist at Moffitt approached him to see if therapy inspired by evolutionary theory might work to fully weed out cancer from children newly diagnosed with that same disease. In the highest-risk group, that cancer kills as many as 80 percent of patients within five years.

In October, they met to begin designing a study. This trial will use a more sophisticated evolutionary model to cycle patients on and off of several drugs. The hope is to deploy the additional drugs to kick the cancer while it’s down, and thereby drive it to extinction. It’s an ambitious goal.

For now, Gatenby is most focused on managing advanced cancers in adults, and doing so as a chronic disease. In that sense, he’s challenging the words emblazoned on the outside wall of the Moffitt Cancer Center: “To contribute to the prevention and cure of cancer.” Robert Butler has pondered these words too, which he passes when walking into the building for checkups and treatments. “Certainly, in my case there’s no intention of cure. What we’re doing is control. So that’s not really the correct logo anymore, is it?” he says. Butler tells me about a time when he and some of the Moffitt researchers brainstormed alternative slogans. “We finally came up with ‘Our aim is to make you die of something else’—which I thought was lovely,” he adds. “It’s more true.”

Robert Gatenby photographed at Everson Museum of Art

Roxanne Khamsi (@rkhamsi) is a science writer living in New York and chief news editor of Nature Medicine.

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