The War on Cancer: Lessons from the War on Terror

The war metaphor has become commonplace in discussions about our endeavor to find a cure for cancer. But beyond the power of imagery, this analogy offers the opportunity to highlight lessons that warriors of cancer can learn from the warriors of terror: that more efficient killing of the undesired cells may not always be better. Evidence suggesting that drug-stressed and dying cancer cells can drive tumor progression is almost as old as cancer therapy. But like in warfare until recently, the primary focus in cancer therapy has been, and still is, on how to more efficiently kill. Ever since President Nixon launched the war on cancer in 1971, the war metaphor has offered a convenient communication tool to articulate the ups and downs of our quest for a cure of cancer (1). The repeated use of the war metaphor, however, has directed our attention to the most visible activity of warfare: the use of destructive force which, ironically, military leaders now have recognized as a problem. They have learned their lessons, and here is where the parallels stop: lessons that cancer warriors have yet to learn. Much as indiscriminate carpet bombing has given place to laserguided bombing of the enemy, so are we replacing broadly cell-killing chemotherapy with modern “target-selective drugs” that can take out with molecular precision the critical proteins required for cancer cell survival and expansion while minimizing collateral damage. Yet these celebrated magic-bullet drugs (2) almost universally fail to eradicate the tumor, which typically relapses after a year or less. And when the tumor recurs, it is more malignant and uncontrollable than before (1). The current hope is that with even more precise target-selective drugs that circumvent resistance-conferring mutations and by using clever combinations of such drugs, we will ultimately win the long war against the evasive cancer cells (3). Multi-pronged targeted attacks appear plausible in cornering the tumor cells, as we have seen in anti-viral therapy of HIV, and could conquer drug resistance. But cancer cells are not rigid viral particles whose sole means of evasion is genetic mutation. Cancer cells are plastic. The thousands of normal cell types in the human body, all carrying the same genome, manifest an enormous developmental potential. Could cancer cell exploit such inherent developmental plasticity of metazoan cells to adopt, without mutations, new phenotypes to evade treatment (4)? If yes, then, more effective killing to outrun the Darwinian somatic evolution (5) generally thought to drive the development of therapy resistance in tumor cells, might be the wrong answer to therapy failure. Put more bluntly: what do all cancer drug therapies have in common? Answer 1: they essentially fail to cure cancer. Again, what do all cancer drug therapies have in common? Answer 2: they all seek to perturb, mostly kill, cancer cells. Thus, by pure logics, could killing eo ipso be the problem? In fact, all therapies fall into the broad category of killing or arresting tumor cells, directly through cytotoxic or differentiating therapy, or indirectly via inhibition of angiogenesis, altering the tumor bed or enhancing antitumor immunity. Often, solutions to tough problems come from thinking in a more encompassing category than imagined. Perhaps, questioning the unquestioned notion that “only a dead tumor cell is a good tumor cell”is the first step. This is what cancer biologists and oncologists can learn from lessons learned in the war on terror: to think beyond killing as many enemies as possible. Targeted bombing in the war on terror has only short-term benefits. Unlike traditional warfare against homogenous armies with soldiers marching in unison, the war on terrorists, and by analogy, the war on cancer cells, is more akin to a guerilla war. It is nearly impossible to specifically kill every single one of the bad guys, not even with precision weaponry. Sure, bombing campaigns are often necessary to avert immediate danger by reducing the numbers of enemy combatants. But the inevitably surviving terrorists will recover, regroup, and adapt, emerging even stronger. This is not the passive “selection” of genetically stronger fighters as modern Darwinists might think, but rather the result of an active response by the lucky survivors of an incomplete attack in a rugged terrain. In the same way, targeted therapy of cancer debulks the tumor, providing urgently needed relief. But like the guerilla combatants in the mountains, cancer cells are too diverse and too disperse, such that highprecision targeted attacks almost always will allow some cancer cells to survive in the tissue. These residual cells will re-emerge as a recurrent tumor – this time resistant to the drug and more malignant than before. But the parallels between the war on terror and the war on cancer end when it comes to the lessons learned. In the course of history, generals have learned a lesson that cancer researchers have not yet learned. In the wars on terror, military commanders have now recognized that surviving a drone attack energizes people more than any propaganda can (6), creating new fighters, more numerous and fiercer than before