Richard Nixon initiated the War on Cancer by signing the National Cancer Act of 1971. It’s been 42 years since then, so why haven’t we defeated cancer? Scientifically, the War on Cancer has been a smashing success: We understand the basic biology of cancer better than that of any other common disease. And now we're beginning to understand why we haven’t cured cancer. Researchers have lately been working to comprehensively map cancer genomes. Their results show just how frustratingly complex cancer really is, and how hard it is going to be to find widely effective cures.
Cancer is caused by genetic mutations that drive cancer cells to toss aside all natural checks and reproduce themselves uncontrollably. Mutations that drive this process are called “driver mutations.” In the decades after National Cancer Act, scientists noticed that driver mutations seemed to occur in the same handful of genes over and over. Not surprisingly, most of the genes that pick up driver mutations play key roles in cell reproduction. This finding led to the idea that cancer is caused by damage to a select group of cell-reproduction genes, and that different cancer types could be cured by designing smart drugs that specifically target those mutated genes.
After billions of dollars and many overly ambitious projections of victory, it is becoming clear that the War on Cancer can’t be won with a massive offensive assault.
The poster child for this idea, and one of the earliest successes, is the drug Gleevec, which directly targets the protein produced by a particular mutation common in certain leukemias. Most chemotherapy is a blunt instrument that indiscriminately poisons any rapidly reproducing cells in the patient’s body. Gleevec and other smart drugs are more like laser-guided bombs, potentially able to destroy the cancer target while limiting damage to healthy cells. Ideally, the result is a more effective cancer treatment with fewer side effects.
Smart drugs have been highly successful in very specific cases, but they haven’t been the turning point in the War on Cancer that we hoped they would be. Many cancers turned out to be invulnerable to drugs that target a single mutation. Scientists reasoned that if we could find more cancer driver mutations, we could design new drugs that target those mutations and thus successfully treat a much wider range of cancers. And so the idea of systematically analyzing cancer genomes was born.
CANCER GENOME PROJECTS ARE the latest front in the War on Cancer. The U.S. National Institutes of Health created The Cancer Genome Atlas (whose acronym, TCGA, consists of the abbreviations for each of the four chemical letters in DNA), and the United Kingdom’s Wellcome Trust is assembling the Catalog of Somatic Mutations in Cancer (COSMIC). The goal of projects like these is to exhaustively map out the genetic terrain of cancer by identifying every mutation in the genomes of tumors from tens of thousands of cancer patients. The hope motivating these projects was that scientists would discover a core set of cancer driver mutations for each type of cancer, mutations that could be targeted with smart drugs.
What researchers have discovered instead is that cancer is a much more fiendishly complicated genetic mess than we ever imagined. Instead of a handful of cancer-causing driver mutations for each cancer type, scientists have found that there are many different genetic paths to the same cancer. Many driver mutations for a particular cancer type occur in less than 20 percent of cancers of that type, which means that drugs targeted at that mutation will only help a minority of patients. A recent review of the subject noted that the COSMIC project has cataloged more than 800,000 mutations, covering nearly every gene in the human genome. The authors of the review suggested that “the cast of genes involved in any single cancer type will be in the neighborhood of 50–100.”
Cancer genome projects are now running into the problem common to all big data projects: sorting out the signal from the noise. Many cancer genomes are filled with mutations. Some are drivers, but others are merely “passenger mutations” that just come along for the ride and have no functional role in causing disease. Driver mutations are expected to be common, showing up over and over in different patients, while specific passenger mutations should be rare and occur no more often than random chance. However, sorting out drivers from passengers turns out to be not so easy; scientists are finding that rare driver mutations can account for a large fraction of cancers.
So is there any hope at all of finding a cure for cancer? After more than 40 years, billions of dollars, and many overly ambitious projections of victory, it is becoming clear that the War on Cancer can’t be won with a massive offensive assault; the reality is that we are fighting a guerrilla war. Cancer genome projects are providing us with a high-resolution map of the terrain, but it is more difficult than we thought to pick out the important high ground. There will be no dramatic announcement that we’ve cured cancer. What we’ll continue to see is what has happened ever since the National Cancer Act of 1971: incremental, but steady progress, progress that is sometimes hard to see in our aging, increasingly cancer-prone population, but progress that nevertheless will alleviate suffering, prolong lives, and, in some cases, produce cures.