Might cancer be a natural part of a cell's landscape?by Philip Ball / February 17, 2016 / Leave a comment
Scroll to the bottom for an analysis of the seven challenges Caner Research UK has set itself
Medical science is making huge advances in treating cancer. Figures released in February by Cancer Research UK showed that, since 2003, the chances of dying from the disease have fallen by 10 per cent. Increases in screening for the disease along with improved treatments mean that thousands of people in Britain have been saved from an early death.
But cancer is a disease like no other. It isn’t caused by a lone pathogen or genetic defect, so there is no single obvious point of attack in treating it. Unlike that other major killer, cardiovascular disease, it is not confined to any particular organ or tissue. In general, it has both genetic and environmental triggers.
These are some of the reasons why cancer is so hard to combat, and why the approaches are so diverse. But there is a growing sense that cancer is not so much a disease or even a malfunction—it is the dark side of being alive, a hazard lurking in the molecular mechanisms of our cells much as road networks harbour the potential for traffic jams. That’s one reason why it makes little sense to speak of a “war on cancer”: military metaphors, almost impossible to avoid in discussing the treatment of disease, seem particularly inappropriate when the target is not, say, a virus or bacterium, but our own biology. The scale of the problem has been reflected in Cancer Research UK’s (CRUK) call last October for research that will meet seven “Grand Challenges” (see box on p67). Some of the targets are specific—for example, to eradicate cancers caused by the Epstein-Barr virus, which triggers 200,000 new cases and claims 140,000 lives worldwide each year. Others—to discover how unusual patterns of mutation are induced by different cancer-causing events, for example—reveal our ignorance by their very breadth.
But these grand challenges highlight only a part of what remains unknown. As Gerard Evan, a biochemist at the University of Cambridge, recently wrote in Nature, “despite 45 years of insight into the molecular processes of cancers, we still do not really know how therapies exploit the vulnerabilities of different cancers, or even why such vulnerabilities exist.” In other words, even though we have drugs and other therapies, we don’t actually know why they work. CRUK’s challenges are valid and important, but no one imagines that they will “solve” the problems of cancer.
Cancers are breakdowns in the regulation of the cell cycle, the normal process by which new cells are generated, mature, age and die. Our cells are constantly going through this process: around 50-70bn cells in our body die each day. If the cycle is disrupted, cells may proliferate unchecked, leading to the growth of a tumour. So it is unsurprising that some of the key genes involved in cell cycling, such as those called Myc and p53, are implicated in cancers. The p53 gene, for example, acts as a brake on the cycle, slowing it down or killing the cell. In this way, it serves as a tumour suppressor, and many cancers result from malfunctions—mutations, for example—of p53 that permit uninhibited cell growth.
About half of all cancers seem to be associated with mutations of p53. The gene is a line of defence: it is activated by a variety of potential triggers, such as exposure to oxidants, ultraviolet light, or other chemical or physical factors that can damage DNA and cause mutations. When such potentially carcinogenic damage happens, p53 is “switched on” either to initiate DNA repair (the study of which won the 2015 Nobel prize for chemistry) or to induce the death of the cell if the DNA is beyond mending. All this means that both the activation of p53 and its knock-on effects are complicated. Likewise for Myc: it has many triggers and many effects.
“Even though tumours arise from within the body rather than outside it, might we not encourage our immune system to react to them too?”
Because of this complexity, cancer treatments that aim to tweak the behaviour of p53 or Myc are hugely challenging; it’s not as if they are simply on/off switches for tumours. That’s true of genetic approaches generally: the role of genes is important, but complicated. The BRCA1 gene is another tumour suppressor involved in DNA repair, in which mutations can increase a woman’s susceptibility to breast and ovarian cancer. But there are hundreds of identified mutations, and the biochemical routes by which the gene exerts its effects are multiple and complex. So it’s not easy to extrapolate from genetic testing of BRCA1 to an assessment of risk, let alone a treatment plan. One cancer specialist told me, after Angelina Jolie announced in 2013 that she had had a double mastectomy because she carried a “faulty” version of BRCA1, that this was not necessarily the best decision—there might have been other, non-surgical ways to mitigate the risk.
While genetic studies have understandably played a major role in research, some researchers feel that their clinical value will always be limited. Sure, our genome might contain clues about our vulnerability to certain types of cancer, but strategies for both prevention and cure might be better directed elsewhere.
One of the most promising new approaches aims to make use of the body’s immune system. The immune response is a general-purpose defence, responding and adapting to insults ranging from allergens to viruses. Even though tumours arise from within the body rather than outside it, might we not encourage our immune system to react to them too?
The idea has been around for decades, but only in the past five years or so has it started to pay off. Cancer immunotherapy, as it is called, was declared in 2013 by the journal Science to be the scientific breakthrough of the year. Clinical trials have shown the value of the approach for various types of cancer, and some patients treated this way have made remarkable recoveries from previously fatal conditions: a woman recovering from a lung tumour the size of a grapefruit, a six-year-old child rescued from near-terminal leukaemia.
The idea is to take the gloves off the immune system so that it can attack tumours with full force. This involves using antibody drugs—proteins designed to latch on to specific target molecules—that bind to T cells, the white blood cells that control an immune reaction. When the drug binds, it suppresses the usual processes that moderate and restrict the activity of T cells, unleashing a full-blown immune attack—through which even quite advanced cancers can be brought back into remission. One of these drugs, called Ipilimumab, is now licensed by the United States’s Food and Drug Administration (FDA) for use against skin cancers. A course of treatment costs over $100,000 but, especially when used in conjunction with other immune-boosting drugs, the results have been encouraging.
There’s no doubt now that the immune response can fight cancer. But there’s still a lot of research needed to understand how that process operates, to avoid nasty side effects (there’s a good reason why the immune system comes equipped with brakes) and to fine-tune the process. One approach under development involves genetically modifying a patient’s T cells so that they will attack tumour cells specifically, leaving others alone. Another is to tweak the microbes in a patient’s gut to boost the power of the drugs: certain gut bacteria make the immune system more responsive, but not everyone has them. T-cell therapy has very recently shown to have extraordinary promise for treating blood cancers (leukaemia). In mid-February, researchers at the Fred Hutchinson Cancer Research Center in Washington state reported initial clinical trials in which more than half of the patients treated went into complete remission. For one particular kind of leukaemia, fully 94% of the patients—most of whom would have been diagnosed as terminally ill—saw their symptoms vanish.
Our bodies can also acquire immunity by vaccination. Vaccines are biological agents similar to those that cause a pathological condition, but harmless in themselves. Some cancers are triggered by external pathogens: for example, several types of cervical cancer are caused by infection with the human papilloma virus (HPV). There are already anti-cancer HPV vaccines in use: in Britain, one called Gardasil is now routinely offered to girls aged 12 to 13.
Most cancers, however, are non-viral. Might vaccines nonetheless protect against them too? That’s the target of another of the CRUK challenges. In general, the aim is to actually use viruses for defence, engineering them to attack tumour cells. As well as this selective targeting—the modified viruses will only replicate in cancer cells—the approach has the advantage that it sets its own dose to the appropriate level: the bigger a tumour, the more of the virus is produced. “Most viruses have potential utility as anti-cancer agents, provided they are understood and adapted in the right way,” says Stephen Russell, a professor of medicine at the Mayo Clinic College of Medicine in Rochester, New York.
The first anti-cancer viral drug, a genetically modified herpes virus called Imlygic, has just received FDA approval. Its main role is actually a form of cancer immunotherapy: the Imlygic virus infects skin cancer tumours, where it produces an immune-boosting protein that helps the body attack the rogue cells. But excessive production of this protein can also in itself destroy tumour cells simply by filling them up until they rupture. Imlygic is undergoing clinical trials for other cancers too, including pancreatic and breast cancer. “I expect it to become a major component of cancer therapy for most cancers, and to become a preferred ‘frontline’ therapy within the next 10 to 20 years,” says Russell. The idea here is to get smarter about attacking tumours. Traditional methods have been necessarily but woefully crude, resorting either to surgery or to toxic drugs that hopefully hit tumours harder than the rest of the body—hence their serious side-effects. The first chemotherapies really did kill patients, and even now only a small amount of anti-cancer drugs typically end up in the tumour; the rest is taken up by other tissues or just flushed from the body.
The idea here is to get smarter about attacking tumours. Traditional methods have been necessarily but woefully crude, resorting either to surgery or to toxic drugs that hopefully hit tumours harder than the rest of the body—hence their serious side-effects. The first chemotherapies really did kill patients, and even now only a small amount of anti-cancer drugs typically end up in the tumour; the rest is taken up by other tissues or just flushed from the body.
“Employing the precision of nanotechnology to repair the human body looked at first as though it could supply a magic bullet”
So we need to target tumours more effectively. For example, drugs could be tethered to molecules that will recognise and stick to cancer cells. Better delivery systems are also needed to carry large drug molecules such as proteins, which are potentially powerful anti-cancer drugs that can zero in on specific biochemical pathways rather than just wreaking indiscriminate damage to cells. Large molecules aren’t easy to administer, however, since they are fairly insoluble and, once in the bloodstream, quickly broken down by the immune system. That is why CRUK has made improved delivery methods for such drugs another of its grand challenges.
Better drug delivery is one strand of a much-vaunted field of “nanomedicine,” which combines the expertise of chemists, materials scientists, pharmacologists and cell biologists. Employing the precision of nanotechnology (engineering at the scale of a nanometre, one billionth of a metre) to repair the human body looked at first as though it could supply a magic bullet for cancer and other diseases, but early promise has given way to a sober appreciation of the challenges. “This is a really hard problem,” says Peter Searson, Director of the Institute for NanoBioTechnology at Johns Hopkins University in Baltimore.
“One of the problems is that typical drug targets in tumour cells—proteins that are produced more rapidly in quickly replicating cells, or ones involved in the growth of blood vessels (which tumours need to survive)—are also found in lower levels in many other cells. So the targeting is never perfect,” Searson says. And nanoparticles loaded with a drug are still imperfect delivery systems: they can get broken down or cleared from the body, or become unstuck from their targets. Yet little is known about these processes because traditional methods of gauging cancer drugs aren’t designed to measure such fine details. Without such information, it’s hard to develop a good set of design rules for this kind of medicine. Indeed, the whole concept of designing drug delivery here—as opposed to the traditional trial and error of finding new anti-cancer drugs—is still in its infancy.
As a result, while the literature is full of papers describing all kinds of fancy nano-systems—for example, particles tailored with atomic precision and equipped with complicated molecular-scale mechanisms for loading and unloading drugs—there are only six “nanomedicines” approved by the FDA for treatment of solid tumours, and all of these are rather low-tech. “There’s a reality gap between what we can build and getting them into the clinic,” says Searson. What’s more, while kudos (and publishability) in science depends on developing something new, the most effective systems are likely to be those that rely on materials already well tested and FDA-approved. “There’s a lot of unglamorous work that needs to be done to advance the field,” says Searson.
Perhaps it will be more fruitful in the long run to harness nanotechnology for ultra-precise detection and analysis. Cancer immunotherapy is already benefiting from nanoscale devices that can analyse tissues at the level of individual cells, both to better understand which T cells are most effective at killing cancer cells and to map out the diversity of cell types within tumours. Other devices like this could detect cancers at a very early stage. One of the most powerful predictors of a successful outcome in cancer treatment is simply the time of diagnosis: the sooner the danger is spotted, the more likely it can be averted. There are warning signs in the body well before the traditional symptoms of pains, lumps and fatigue: changes in the activity pattern of genes in cells that are becoming cancerous, say, and consequent changes in metabolism. Such telltale signatures are initially very faint: the concentrations of cancer-marker molecules in the blood are tiny. But in principle they could be picked up by tests that are both sensitive and diverse enough, which becomes possible with nanotechnological chemical sensors. Already, researchers at the University of Cambridge have used nanoscale fabrication to make an “electronic nose” that can detect biochemical signals of lung cancer in a simple breath test. It’s not fantasy to imagine that one day nanodevices permanently and unobtrusively implanted in the body might monitor the bloodstream continuously, signaling an alarm when the faint chemical signs of incipient cancer are detected.
Fighting cancer will always be a many-pronged offensive. Among other things, it requires improvements in understanding the biochemical mechanisms involved, in drugs and ways of delivering them, in ways of harnessing the body’s own defences, and in methods of detection. If one hears little talk these days of a “cure for cancer,” that is not just a matter of being realistic but an acceptance that the notion of cure is too simplistic for such a multi-faceted problem.
But it may be that there is not exactly something to “cure” here anyway—it might be like saying that we could “cure” the polar ice caps from melting. That’s something we’d like to prevent, of course, but molten is the natural state of ice under the right—or wrong—circumstances. Cells exist in a “dynamical” state of ongoing biochemical reactions, like a machine operating by the intermeshing of many moving parts. In this view, a cancerous state is merely an alternative way that cells can work—in some ways (and herein lies the problem) an extremely effective one, without the usual checks on growth and proliferation. By the same token, the earth’s climate can persist in a healthy state or it can enter a pathological one from the human perspective, such as an ice age or an overheated, greenhouse world. Within the science of “dynamical systems,” stable states into which a complex system can fall are called attractors. The challenge, then, is to avoid the cancer attractor.
In this view of cancer, the switch from healthy to tumorous cell growth is not so different from the way stem cells become specialised into particular tissue cells: a process that involves no changes to genes, but rather a change in the way they interact with one another, which can be triggered by external influences. Jin Wang, a professor of chemistry and physics at the State University of New York, Stony Brook, points out that this perspective unifies the “genes vs environment” picture of cancer’s origins, allowing one to seek an understanding not just in genetic mutations but in non-genetic breakdowns in communication within the network of genes controlling the cell cycle. This picture isn’t yet mainstream, and it’s not easy to see yet how it might translate into clinical applications. But Wang’s hope is that it might highlight comprehensive strategies for prevention and cure that alight on several targets rather than just one.
The dynamical-systems view, then, portrays cancer as a natural part of the cell’s landscape. That need not be a fatalistic conclusion. It means, rather, that the heroic yet misleading idea of a war to be won must be replaced with that of a problem to be managed. CRUK’s grand challenges are a useful but inevitably incomplete list of what that management might entail—and a reminder of why cancer is different.
The challenges—and the reality
Cancer Research UK has set itself seven challenges. How hard will it be to reach these goals? Some of the seven are easier than they seem—but most are harder, says Philip Ball
1—Develop vaccines to prevent non-viral cancers Research is already under way. It’s a complex problem that will probably have no single solution, but if it can be cracked, the benefits could be immense for a wide range of cancers.
2—Eradicate EBV-induced cancers from the world Most people carry the virus (a member of the herpes family), but it is mostly relatively harmless. However, it causes around 200,000 cancer cases, and 140,000 fatalities, globally each year. This is a rare instance of a cancer cause that could in principle be eradicated, as some other viruses have been.
3—Identify new targets for cancer prevention by understanding how unusual patterns of mutation are induced by different cancer-causing events This is a very broad challenge: to identify hitherto unknown carcinogens and health factors underlying cancer. It’s an epidemiological problem, complicated by the fact that some cancers may be induced by several factors, not just one.
4—Distinguish between lethal cancers that need treating, and non-lethal cancers that don’t Besides the existence of benign tumours, not all cancers are life-threatening; some will disappear naturally with time. In such cases, administering drugs with nasty side effects only harms the patient. Yet diagnostic tests such as x-rays can’t yet always tell the difference.
5—Map the molecular and cellular tumour micro-environment in order to define new targets for therapy and prognosis Tumours are complex communities, not just clusters of identical “cancer cells.” To attack them effectively and efficiently, we need to know more about their structure: a 3D map that might be used, for example, to monitor treatments. This is a challenge demanding interdisciplinary work, for example to develop new analytical tools.
6—Develop innovative approaches to target the cancer super-controller Myc This too is a very broad challenge. Mutant, over-active forms of the Myc gene can help tumours survive, so drugs that block it could be very useful. But our understanding of the gene’s roles is still limited, and CRUK says that this goal is not just technical: it needs new thinking too.
7—Deliver biologically active macromolecules to any and all cells in the body to effectively treat cancer This is a more tightly focused objective—a matter of better drug delivery that will need to draw on the skills of chemists and materials scientists, as well as cell biologists and cancer pharmacologists. It is arguably one of the challenges in which near-term progress seems most likely.