– Robert A. Gatenby is Chairman of Radiology and Integrated Mathematical Oncology at the H. Lee Moffitt Cancer Center.
By Robert A Gatenby
TAMPA – Patients and politicians increasingly demand a “cure” for cancer. But controlling the disease may prove to be a better strategy than striving to cure it.
A century ago, the German Nobel laureate Paul Ehrlich introduced the concept of “magic bullets” – compounds engineered to target and kill tumor cells or disease-causing organisms without affecting normal cells. The success of antibiotics 50 years later seemed to validate Ehrlich’s idea. So influential have medicine’s triumphs over bacteria been that the “war on cancer” continues to be driven by the assumption that magic bullets will one day be found for tumor cells if the search is sufficiently clever and diligent.
Yet lessons learned in dealing with exotic species, combined with recent mathematical models of the evolutionary dynamics of tumors, indicate that eradicating most cancers may be impossible. Trying to do so, moreover, could worsen the problem.
In 1854, the year Ehrlich was born, the diamondback moth was first observed in Illinois. Within five decades, the moth had spread throughout North America. It now infests the Americas, Europe, Asia, and Australia. Attempts to eradicate it using chemicals worked only fleetingly. In the late 1980’s, biologists found strains that were resistant to all known insecticides.
So farmers abandoned their efforts to eliminate the 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 by strategies that restrict the population growth of pests but do not attempt to eradicate them
The ability of tumor cells to adapt to a wide range of environmental conditions, including toxic chemicals, is similar to the evolutionary capacities demonstrated by crop pests and other invasive species. As in the case of the Diamondback moth, successful eradication of disseminated cancer cells is rare. But despite the paucity of success, the typical goal in cancer therapy remains similar to that of antimicrobial treatments – killing as many tumor 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.
Some types of cancer – for example, Hodgkin’s lymphoma, testicular cancer, and acute myeloid leukemia – can be consistently cured using aggressive chemotherapy. But these malignant cells seem to be particularly responsive to “treatment.” Just as invasive species adapt to pesticides, most cancer cells adapt to therapies. Indeed, the parallels between cancerous cells and invasive species suggest that the principles for successful cancer therapy might be found not in the magic bullets of microbiology but in the evolutionary dynamics of applied ecology.
Recent research suggests that efforts to eliminate cancers may actually hasten the emergence of resistance and tumor recurrence, thus reducing a patient’s chances of survival. The reason arises from a component of tumor biology not ordinarily investigated: the cost of resistance to treatment.
Cancer cells pay a price when they evolve resistance to chemotherapy. For example, to cope with toxic drugs, 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 signaling needed for proliferation and survival, a cell might adapt by activating or following alternative pathways. All these strategies use up energy that would otherwise be available for invasion into non-cancerous tissues or proliferation, and so reduce a cell’s fitness.
The more complex and costly the mechanisms used, the less fit the resistant population will be. That cancer cells pay a price for resistance is supported by several observations. Cells in laboratory cultures that are resistant to chemotherapies typically lose their resistance when the chemicals are removed. Lung cancer cells that are resistant to the chemotherapy gemcitabine are less proliferative, invasive, and motile than their drug-sensitive counterparts.
Although resistant forms are commonly found in tumors that haven’t yet been exposed to treatment, they generally occur in small numbers. This suggests that resistant cells are not so unfit that drug-sensitive cells completely out-competed them, 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 cells. When a large number of sensitive cells are killed, say, by aggressive therapies, resistant types can proliferate unconstrained. This means that high doses of chemotherapy might actually increase the likelihood of a tumor becoming unresponsive to further therapy.
So, just as judicious use of pesticides can control invasive species, a therapeutic strategy designed to maintain a stable, tolerable tumor volume could improve a patient’s prospects for 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 chemotherapy. 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 tumor volume, the animals, though not cured, survived for a prolonged period of time.
Designing therapies to sustain a stable tumor mass rather than eradicate all cancer cells will require a 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 need to understand the evolutionary dynamics of resistant populations, and design strategies to suppress or exploit the adapted characteristics.
Of course, cancer researchers should not abandon their search for ever-more-effective cancer therapies, even for cures. But it may be time to temper our quest for magic bullets and recognize the cold reality of Darwin’s evolutionary dynamics. Medicine’s goal of a glorious victory over cancer may need to yield to our recognizing that an uneasy stalemate may be the best that can be achieved.
