WHY NATURAL SELECTION AND NOT JUST MUTATIONS CAUSES CANCER … AND HOW CU DOCTORS ARE HARNESSING EVOLUTION TO STOP IT.

The other day, I was chaperoning a 2nd grade field trip to the Denver Museum of Nature and Science when the conversation turned, as it usually does, to the question of whether animal X would beat animal Y in a fight. The combat in question was that of Daeodon, a giant, carnivorous pig native to North America, Eurasia and Africa during the Miocene period, versus the tyrant lizard, T-Rex. If you’ve been to the museum, you know that the monster pig is the stuff of nightmares. But the answer was pretty obvious: T-Rex would totally win. Hands down.

The kids were pretty quick to the conclusion that not only would T-Rex make a quick snack out of Daeodon, but the tyrant lizard would easily munch on the short-faced bear too, largest of the Ice Age carnivores. In fact, when you look across the whole potential spectrum of theoretical mammal-versus-dinosaur duels – from the tiniest little proto-mammal versus its chicken-sized dinosaur ancestor, to packs of wolves versus packs of velociraptors – it’s pretty obvious that the dinosaurs would win every time.

Which brings up an important question: Why did the dinosaurs lose?

The reason, as you know, is that 65.5 million years ago a six-mile diameter space rock smashed into present-day Chicxulub, Mexico, detonating with the force of 100 teratonnes of TNT. The landscape changed overnight. In fact, the landscape became night. A dust cloud blocked the sun for a year and the Earth was plunged into winter. The dinosaurs took this badly (they just would, wouldn’t they?).

But it was great for furry little creatures like the marmot-sized alphadon. Sure, alphadon existed in the Cretaceous – one of a few proto-mammals to eke out a tenuous existence – but its population was kept in check by its more toothsome and scaly dinosaur cousins. That is, until the asteroid kicked the earth into the Cenozoic. With the asteroid, warm blood and thick fur made alphadon suited to the new normal. Picture it: Sixty-six million years ago, the marmot revolution became reality.

According to University of Colorado Cancer Center Associate Director for Basic Research, James DeGregori, PhD, the mammals’ meteoric takeover models the way cancer claims the human body.

“Healthy cells are perfectly optimized for a healthy tissue ecosystem. They are the most fit. In fact, they are so optimized, that most any mutation makes them less fit. In this tissue ecosystem, healthy cells out-compete cancer cells for the body’s resources and thus keep cancer in check. As we age, though, the tissue ecosystem changes. Now healthy cells may no longer be optimized to these new surroundings. Now cancer cells, with their ability to mutate and adapt, may be able to generate cells with a better fit. It is this changing tissue ecosystem and not just the occurrence of ‘new’ mutated cancer cells that lets the disease develop,” DeGregori says.

This line of thinking challenges the more basic model of oncogenesis that has domi­nated the field of cancer research for 50 years. In the traditional model, the longer you are alive, the more time you have for a chance set of mutations to cause cancer. Think about it like playing dice: The more times you roll, the more chance you have of shooting a double six. This line of reasoning makes intuitive sense: We all know that mutations cause cancer cells and the older you are, the higher your chance of developing the disease. Scientists refer to this as the “mutation accumulation” model.

Only, scientists have struggled with some pretty significant holes in this line of rea­soning – actually, the holes are more like tunnels big enough to drive a truck through.

Peto’s Paradox

One of these holes is big enough to have a nifty name – it’s called Peto’s Paradox. Basically, the paradox says that if cancer is due to random activating mutation, larger animals with more cells should be at greater risk of developing the disease earlier in their lives. Why then do mammals of vastly different sizes and lifespans all seem to develop cancer mostly late in life?

“Blue whales have more than a million times more cells and live about 50 times longer than a mouse, but the whale probably has no more risk than a mouse of devel­oping cancer over its lifespan,” DeGregori says. (Although admittedly, it would be hard to prove this in the laboratory, unless it was a very, very big laboratory.)

It’s as if the whale’s many cells are rolling more genetic dice – meaning more chance for it to roll the “double six” of a cancerous super cell. But working with CU Cancer Center research instructor Curtis Henry, PhD, DeGregori shows that cancer cells aren’t “super” at all. Again, healthy cells are optimized for healthy tissue – the genetic changes that cause cancer actually make these cancer cells less fit for their surroundings. That is, unless the surroundings are adjusted.

Here’s an example: The DeGregori lab shows that inflammation in the bone marrow provides conditions in which cancerous blood stem cells are more fit and thus can out-compete healthy blood stem cells. Here’s the important part: chronic bone marrow inflammation is associated with age. When DeGregori and Henry removed the ability of mice to create inflammation, even old mice stayed free of leukemia. It was not just mutation and not just age that was most associated with cancer – it was inflammation.

This provides a solution to Peto’s Paradox: The whale’s cells may roll more double sixes, but in healthy tissue, the cancer cells they create naturally die out. It is only a disturbed tissue landscape in both whale and mouse in which cancer cells can out-compete healthy cells. And disturbed tissue landscape occurs late in life. And Peto’s Paradox isn’t the only hole in the accumulation of mutations model.

Cancer risk isn’t linear

Another hole is the fact that cancer risk doesn’t increase at a constant rate over time – it’s not just rolling dice. For example, there is a leukemia spike in very young children, then rates stay low through middle age before increasing exponentially in older adults. Instead of the progressively increasing risk predicted by the accumulation of mutations model, leukemia rates go up and down and up again like a roller coaster.

Working with postdoctoral researcher Andrii Rozhok, PhD, DeGregori blames the leukemia spike in young children on another evolutionary force, called “genetic drift.”

Genetic drift is the role of chance – the possibility that despite being less fit, a lucky organism happens to survive to reproduce and eventually shift the genetic makeup of the population. Importantly, the influence of drift is greater in small populations.

“Imagine if you flip a coin 10 times. You would not be too surprised if seven of 10 flips gave you heads. In fact, the odds are about one-in-six. But if you flipped the same coin 1,000 times, the odds of getting 700 heads would be much smaller – less than one in a million,” DeGregori says. “Basically, the more trials we do, the less chance plays a role.”

Now replace these coin flips with a population of cells. A young child has relatively few blood stem cells – with only a few “coin flips” a less fit cancer cell can get lucky. An adult has far more blood stem cells – this blunts the influence of drift and means that to cause cancer in a healthy adult, a less fit cancer stem cell would have to be really, really lucky.

Again, seeing cancer through the lens of evolution explains a gap in the accumulation of mutations model: The spike in cancers among very young patients is likely in part driven by genetic drift in which less fit cancer cells have a better chance of getting lucky in a smaller population.

Now that we’ve seen how evolution drives the development of cancer, let’s look at how doctors are exploiting the same forces to kill it.

Cancer evolution in the clinic

Aging-associated inflammation isn’t the only thing that affects our tissue ecosystem. On the downside, things like smoking, radiation exposure, obesity and alcohol damage tissues … and cancer rates rise accordingly. On the upside, doctors can affect the tissue landscape, too. In a roundabout way, this is a strategy of cancer therapy: Doctors can introduce drugs that make the body’s ecosystem more hostile to cancer cells than to healthy cells. But then why, after a period of control, do these cancers so often restart their growth even in this ecosystem that selects against them? Again, the answer lies in evolution.

“Diversity exists in cancers and is generated every time the cancer cells replicate. That diversity sets the stage for evolution in the environment of any active drug,” says D. Ross Camidge, MD, PhD, Joyce Zeff Chair in Lung Cancer Research at CU Cancer Center and director of thoracic oncology at University of Colorado Hospital.

What Camidge means is that in many cancers, evolution may be more than a fight between healthy cells and cancer cells. For example, some cells in a lung cancer that we call ALK-positive may have a dominant cancer-driving abnormality in a gene called ALK. But other cancer cells living right next to them may have ALK and some addi­tional genetic changes capable of driving the cell. At diagnosis, these other cells have no specific advantage – you don’t need two steering wheels in a car. However, when doctors use the drug crizotinib to “select against” ALK-positive cells, this may clear the path for the other kind of cancer cells to make use of their extra potential to keep driving, and so the new “double driver” cells become dominant in the tumor.

Thus the competition is not just between healthy cells and cancer cells, but between all the cell types – healthy cells, ALK-positive cancer cells, and all the other populations of cancer cells fighting for resources and survival in the diverse ecosystem of the body.

The realization that a tumor may contain a couple or even many types of competing cancer cells has very real treatment implications. As Camidge explains, “This suggests the use of rebiopsies to sample growing lesions to discover the weaknesses of the newly dominant cell population so that we can use or develop new drugs or drug combina­tions to target these emerging populations.”

And second, Camidge describes a creative new strategy that uses evolution to pit types of cancer cells against each other: “When targeted therapy controls the dominant cancer, a subtype that is less fit but is resistant to the drug may supplant the original cancer. But when you stop the targeted therapy and, for example use a less selective therapy like che­motherapy, you reinstitute the landscape that favored the first cancer. Now if the cancer grows during treatment with nonselective chemo, the original cancer may once again be the form that out-competes and controls the drug-resistant subtype. At that point, after a targeted therapy holiday, you can re-challenge a tumor with the first, targeted therapy and gain a second response – a second honeymoon with the original drug,” Camidge says. This innovative and promising strategy is in use now in the clinics of CU Health.

Equally exciting is new thinking that is trying to push active interventions even earlier in the cancer’s evolutionary path.

Staying a step ahead of evolution

“When you perturb a cancer cell in the lab, you see the cell adapt very rapidly, in minutes,” says Robert C. Doebele, MD, PhD, associate professor of Medical Oncology at the CU School of Medicine. In other words, when doctors make a hostile ecosystem, cancer cells adapt to the change – think of it like dinosaurs sprouting fur. “A subset of the cells rapidly turn on other programs that allows them to survive, even if they aren’t immediately ready to grow,” Doebele says.

The thing is, some cancer cells do this better than others. This is one reason we see varying results from targeted therapies. Some patients have cancers that are slow to evolve and these patients see strong, long-lasting responses to therapies that select against a cancer cell’s genetic needs. Other patients, with seemingly the same cancer, treated with the same drug, happen to have cancers that are quicker to evolve and these patients manifest more modest tumor responses.

“People have been so impressed by the responses to targeted therapies that we over­looked the fact that we aren’t getting 100 percent response in all patients. We’ve had this success, but now it’s time to go back and ask how we take it to the next level. Maybe we can move the science beyond treating with one drug and waiting until the tumor evolves and progresses before trying to figure out what makes it resistant,” Doebele says.

For example, Doebele’s lab has now shown that one particular pathway, the Epidermal Growth Factor Receptor (EGFR) pathway, is commonly used by lung can­cers to turn on an immediate survival signal in the face of an active targeted therapy.

“For several years we’ve known that nearly 90 percent of lung cancers express high levels of the EGFR protein, but that most lung cancers are not sensitive to inhibiting just that one pathway. If it’s not functioning as a driving pathway, but, rather, an imme­diate survival pathway to shield a subset of cancer cells from active treatments, its high frequency starts to make a lot more sense.” To explore this in the clinic, Doebele is now leading a clinical trial looking at combining an ALK inhibitor with a short course of an EGFR inhibitor.

DeGregori says it this way: “Humans have one advantage over cancer. We have some ability to predict the future. Cancer does not.” The crystal ball is still under construction. But with work, we may be able to take one very important step ahead of cancer’s evolu­tion, treating not only the cancer that exists, but the cancer that we predict will exist.

Population reservoirs

When evolution isn’t enough, cancer is willing to wait. Here’s how:

Scientists studying infectious diseases talk about “reservoirs” – species that harbor a disease and can periodically reintroduce it into a population. For example, the reservoir for Ebola may be fruit bats. Doctors, patients and aid workers may select against an Ebola outbreak … but the bats carry the virus and can restart the disease months or years later.

Carol Sartorius, PhD, associate professor in the Department of Pathology at the CU School of Medicine shows that reservoirs are an important evolutionary strategy for cancer, too. For example, as you know, the cells of many breast cancers depend on estrogen. These cancers are called estrogen-receptor-positive, or ER+, and we have very successful medicines to kill cells with this dependence. However, “The interesting thing is that long after therapy has killed ER+ cells, in many cases we can see the resurgence of this population that leads to recurrence of the cancer even five or ten years after treatment ends. Why is that?”

Does the medicine not reach all cells? Is the medicine against ER+ cells not universally lethal? Are some cells not ER+ after all? Do these ER+ cells evolve ways to resist the medicine? Sartorius offers another explanation, namely that, “Cancer stem cells, the cells that can really repopulate a tumor, can become dormant. Maybe there were a couple stem cells sitting there that, long after treatment ends, restart the growth of the tumor.”

These cancer stem cells are the fruit bats of ER+ breast cancer, acting as a reservoir that can reseed the disease once therapy ends. To do so, cancer stem cells may employ yet another evolutionary strategy: symbiosis.

As if it weren’t hard enough to kill competing cancer cells

Symbiosis classically refers to different species working together for mutual gain. For example, clownfish receive protection from anemones and in return the clownfish protect anemones from butterfly fish. Now, it seems that cancer cells can also cooperate to survive threats. Just ask Heide Ford, PhD, professor in the CU School of Medicine Department of Pharmacology.

The Ford lab studies cancer cells that reactivate old developmental programs buried in the depths of their DNA to act more like embryonic cells. One developmental program reactivated by cancer cells is referred to as epithelial-to-mesenchymal transition, or EMT.

There is significant benefit to EMT: “Most tumors have to stay attached to their ‘home’ tissue – if they become detached, they die. But undergoing this transition makes them more motile and aggressive, as well as better able to survive detachment so that they can travel away from the primary tumor and through the body to seed tumor sites elsewhere,” Ford says.

However, these cells that have undergone EMT aren’t especially good at growing the bulk of a tumor and are thus unable to form large metastases at secondary sites. One theory is that cells may undergo EMT to travel and then reverse the process once they arrive. But Ford’s lab has found this reversion may not be necessary – instead, these EMT cells cooperate with cells that have not undergone EMT; they shepherd the ability of these other cells to survive travel through the body, temporarily gifting these cells with the capacity to endure detachment. In return, these enhanced “regular” cancer cells may allow a few rare EMT cells to survive at the secondary site alongside them.

Using evolution to prevent cancer

We’ve seen how evolution drives cancer, helps it survive therapy, and how doctors are using strategies based on evolution to combat cancer. But perhaps the most powerful tool stemming from an evolutionary perspective on cancer is the ability to prevent the disease in the first place.

Let’s go back to our dinosaurs. What would the world be like if the asteroid hadn’t hit? Of course, we can’t know for sure, but it’s likely that for at least a few more million years, giant lizards would have ruled the earth. In other words, if the ecosystem had stayed the same, “healthy” dinosaurs would have continued as the dominant popula­tion. There would have been no marmot revolution.

“We’ve been trying to make drugs that target the products of mutated genes in cancer cells. But if it’s the ecosystem of the body and not only cancer-causing muta­tions that allows the growth of cancer, we should also be prioritizing interventions and lifestyle choices that promote the fitness of healthy cells in order to suppress the emer­gence of cancer,” says James DeGregori.

You can avoid smoking. You may be able to avoid radiation. You can’t avoid aging. But you may be able to avoid some of the cancer-causing effects of aging. For example, do you remember the work of the DeGregori lab showing that cancers are poised to take advantage of age-associated inflammation? Knowing this, the cancer-protective effects of anti-inflammatory drugs, such as aspirin, start to make sense. What else can we do to maintain a healthy environment in order to keep our healthy cells at the top of the body’s food chain? Exercise? Diet? Other Medications? All of this will need to be studied and understood in the light of our increased understanding of the underlying biology of cancer risk.

If cancer is caused by changes to the body’s evolutionary ecosystem, the best way to combat cancer may be to take care of your ecosystem. Rather than playing whack-a-mole with the mammals that sprang up in the wake of the asteroid, a better strategy may be to prevent the impact in the first place.