Patients and politicians anxiously await and increasingly demand a 'cure' for cancer. But trying to control the disease may prove a better plan than striving to cure it, says Robert A. Gatenby.
The German Nobel laureate Paul Ehrlich introduced the concept of 'magic bullets' more than 100 years ago: compounds that could be engineered to selectively target and kill tumour cells or disease-causing organisms without affecting the normal cells in the body. The success of antibiotics 50 years later seemed to be a strong validation of Ehrlich's idea. Indeed, so influential and enduring was medicine's triumph over bacteria that the 'war on cancer' continues to be driven by the implicit assumption that magic bullets will one day be found for the disease.
“The principles for successful cancer therapy might lie in the evolutionary dynamics of applied ecology.”
Yet lessons learned in dealing with exotic species, combined with recent mathematical models of the evolutionary dynamics of tumours, indicate that eradicating most disseminated cancers may be impossible. And, more importantly, trying to do so could make the problem worse.
In 1854, the year Ehrlich was born, the diamondback moth, Plutella xylostella, was first observed in Illinois. Within five decades, the moth, whose larvae feed on vegetables such as cabbage and Brussels sprouts, had spread throughout North America. It now infests the Americas, Europe, Asia and Australia. Attempts to eradicate it using various chemicals suppressed populations only fleetingly and, in the late 1980s, biologists found strains resistant to all known insecticides. Over the past couple of decades, agriculturalists have abandoned efforts to eliminate the diamondback moth. Instead, most now apply insecticides only when infestation exceeds some threshold level with the goal of producing a sustainable and satisfactory crop.
Under the banner of 'integrated pest management', hundreds of invasive species are now successfully controlled with strategies that restrict population growth. By contrast, very few such species have been eradicated. An infestation of the giant African snail, Achatina fulica, was eliminated in Miami, Florida, in the 1960s, for instance. But the snail is easy to catch and, in this case, it had spread to only a few city blocks. Two centuries of experience have shown that the vast majority of introduced species are simply too heterogeneous, too dispersed and too adaptive to be eliminated.
Adapt and conquer
The dynamics of exotic species and invasive cancers differ in many obvious and subtle ways, yet there are important similarities. The invasion of pests involves dispersal, proliferation, migration and evolution — all of which are analogous to the processes that allow cancer cells to spread from a primary tumour into adjacent tissues or to new locations in the body via the lymphatic system or blood vessels. Furthermore, the ability of tumour cells to adapt to a wide range of environmental conditions, including to toxic chemicals, is very similar to the evolutionary capacities shown by invasive species.
As with invasive species, for disseminated cancers, successful eradication is rare. Hodgkin's lymphoma, testicular cancer and acute myeloid leukaemia can be consistently cured using aggressive chemotherapy. But, like the African snail, these malignant cells seem to have characteristics that make them particularly responsive to 'treatment'. Some are unusually homogeneous, for example, so have limited capacity to adapt.
Eradicating the large, diverse and adaptive populations found in most cancers presents a formidable challenge. One centimetre cubed of cancer contains about 109 transformed cells and weighs about 1 gram, which means there are more cancer cells in 10 grams of tumour than there are people on Earth. Unequal cell division and differences in genetic lineages and microenvironmental selection pressures mean that the cells within a tumour are diverse both in genetic make-up and observable characteristics. Additionally, tumours are complex ecosystems: they include normal cells as well as regions of low blood flow and oxygen content where cancer cells are relatively protected from the effects of chemotherapy. If blood flow is poor, for example, so is the delivery of the toxic drugs.
Outwitted by evolution
The typical goal in cancer therapy, similar to that of antimicrobial treatments, is killing as many tumour cells as possible under the assumption that this will, at best, cure the disease and, at worst, keep the patient alive for as long as possible. Indeed, for more than 50 years, oncologists have tried to find ways to administer ever-larger doses of ever-more cytotoxic therapy. But, just as invasive species consistently adapt to pesticides, regardless of concentration or cleverness of design, so too do cancerous cells adapt to therapies. Indeed, the parallels between cancerous cells and invasive species suggest that the principles for successful cancer therapy might lie not in the magic bullets of microbiology but in the evolutionary dynamics of applied ecology.
Support for this idea comes from in vivo experiments, computer simulations and recently developed mathematical models of tumour evolutionary dynamics. These suggest that efforts to eliminate cancers may actually hasten the emergence of resistance and tumour recurrence, thus reducing a patient's chances of survival1.
The reason for this arises from a component of tumour biology not ordinarily investigated: the cost of resistance to treatment. Cancer cells pay a price when they evolve resistance to a particular treatment. For instance, to cope with chemotherapy, a cancer cell may increase its rate of DNA repair, or actively pump the drug out across the cell membrane. In targeted therapies, in which drugs interfere with the molecular signalling needed for proliferation and survival, a cell might adapt by activating or upregulating alternative pathways. All these strategies use up energy that would otherwise be available for invasion into non-cancerous tissues or proliferation, and so reduce the fitness of the cell. And the more complex and costly the mechanisms used, the less fit the resistant population will be.
“Efforts to eliminate cancers may actually hasten the emergence of resistance and tumour recurrence.”
That cancer cells pay a cost for resistance is supported by several observations. Cells in laboratory cultures that are resistant to chemotherapies and to tyrosine kinase inhibitors, a form of targeted therapy, typically lose their resistance when the chemicals are removed2. In cell lines identical except for their sensitivity to tyrosine kinase inhibitors, resistant populations typically grow more slowly than sensitive ones. Lung cancer cells resistant to the chemotherapy gemcitabine are less proliferative, invasive and motile than their drug-sensitive counterparts3,4. Also, although resistant forms are commonly found in tumours that haven't yet been exposed to treatment, they generally occur in small numbers5. This suggests that the resistant cells are not so unfit as to be completely out-competed by the drug-sensitive ones, but that they struggle to proliferate when both types are present.
Our models show that in the absence of therapy, cancer cells that haven't evolved resistance will proliferate at the expense of the less-fit resistant ones. And, when a large number of the sensitive cells are killed, for instance by aggressive therapies, the resistant types are able to proliferate unconstrained. This means that high doses of chemotherapy might actually increase the likelihood of a tumour becoming unresponsive to further therapy.
So, just as the judicious use of pesticides can be used to successfully control invasive species, a therapeutic strategy explicitly designed to maintain a stable, tolerable tumour volume could increase a patient's survival by allowing sensitive cells to suppress the growth of resistant ones. To test this idea, we treated a human ovarian cancer, grown in mice, with conventional high-dose chemotherapy1. The cancer rapidly regressed but then recurred and killed the mice. Yet when we treated the mice with a drug dose continuously adjusted to maintain a stable tumour volume, the animals, although not cured, survived.
The body's predators
Designing therapies to sustain a stable tumour mass rather than eradicate all cancer cells will require a long-term, multilayered strategy that looks beyond the immediate cytotoxic effects of any one treatment. Researchers will need to establish the mechanisms by which cancer cells achieve resistance and what it costs them. They will also need to understand the evolutionary dynamics of resistant populations, and design strategies to suppress or exploit the adapted characteristics.
An obvious problem is the accumulation of toxicity in patients exposed to prolonged, albeit lower, levels of drugs. But in parallel with the diverse array of predators and pathogens currently used to control invasive species, the immune system offers a rich potential source of 'predators' such as T lymphocytes that could sustain a stable cancer population — both by killing tumour cells and selecting for fitness-lowering adaptations.
I am not suggesting that cancer researchers should abandon their search for ever-more-effective cancer therapies, or even for cures. However, instead of focusing exclusively on a glorious victory, they should address the possible benefits of an uneasy stalemate in appropriate situations. Even now, many oncologists agree in principle that therapeutic strategies aimed at controlling cancer could prove more effective than trying to cure it. But the idea of killing not the maximum number of tumour cells possible but the fewest necessary will be difficult for both physicians and patients to accept in practice.
Certainly in a war that is steeped in the tradition of magic bullets and all-out attacks with high-dose chemotherapy, such an approach may seem defeatist. However, in battles against cancer, magic bullets may not exist and evolution dictates the rules of engagement.
Gatenby, R. A., Silva, A., Gillies, R. & Frieden, B. R. Cancer Res. (in the press).
Scappini, B. et al. Cancer 100, 1459–1471 (2004).
Gautam, A. & Bepler, G. Cancer Res. 66, 6497–6502 (2006).
Davidson, J. D. et al. Cancer Res. 64, 3761–3766 (2004).
Izzo, J. G. et al. Mol. Cancer Ther. 5, 2844–2849 (2006).
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