In the New Yorker last month, Malcolm Gladwell wrote elegantly about the euphoria and frustration of cancer drug discovery. Tracing in parallel the path of a modern biotechnology company and a team of doctors in the 1950’s, Gladwell illustrated the unexpected twists and turns that mark every new drug’s journey from laboratory to clinic, in a game where the stakes are literally life and death. The dramatic scene that Gladwell chose to open his piece? The American Society of Clinical Oncology meeting, a huge gathering of cancer researchers where the highly-anticipated results of clinical trials for the next wave of promising anti-cancer agents are presented in a flourish of success or a sigh of failure.
The ASCO meeting this year is being held in Chicago, whose McCormick Place is one of the few convention centers gargantuan enough to hold tens of thousands of researchers from around the world. Throughout the Escher-like hallways of that building, echoes of Gladwell’s opening scene were taking place, with Kaplan-Meier curves – the graph that shows differences between the drug-treated group of patients and the control group – delivering their positive and negative verdicts. Over the weekend, two success stories featured University of Chicago involvement; both were exciting small steps in the battle of science against different types of cancer.
One of the most difficult to treat cancers is also one of the most common: lung cancer, which is newly diagnosed in more than 200,000 people a year in the United States. Lung cancer researchers, including Ravi Salgia of the University of Chicago Medical Center, have been looking for proteins that are behaving badly inside lung cancer cells and that may represent promising targets for cancer therapy. One such target, the enzyme anaplastic lymphoma kinase or ALK, is overactive in a small percentage of lung cancer patients due to a chromosomal translocation – a break in the DNA that produces a dangerous Frankenstein protein called EML4-ALK.
While only 4 percent of patients with lung cancer are positive for EML4-ALK, the mechanism suggests that an inhibitor of the protein may be effective in attacking cancer in that population. Sunday, researchers (including Salgia) presented evidence of that strategy working – an inhibitor of ALK called crizotinib successfully controlled lung cancer in 90 percent of patients enrolled in a small trial. In 57 percent of the patients, tumors actually shrank – an incredible advance in a cancer that is nearly always untreatable. The authors said that a larger, Phase 3 trial is already underway to verify the findings in a larger population.
The success of crizotinib, a targeted therapy for a dangerous chromosomal translocation, contained echoes of a previous triumph in cancer research: Gleevec, a treatment for certain types of leukemia. A descendant of the seminal work of Janet Rowley on the genetic basis of cancer, Gleevec (which inhibits a protein called tyrosine kinase) has been an effective treatment for leukemias as well as other types of cancer. But Gleevec is not infallible; though effective in producing remission in 70 percent of patients with chronic myeloid leukemia (CML), the drug requires high doses and tumors eventually become resistant to the drug.
So the stage was set for new drugs which do the job of Gleevec even better – the “sons of Gleevec,” as my colleague John Easton calls them. Two such drugs were presented at the meeting (or in one case, the day before the meeting) and in the New England Journal of Medicine; one study, of a drug called nilotinib, included our own Richard Larson as an author. The two “second-generation” drugs are merely new inhibitors of the malformed kinase targeted by Gleevec, but early returns show they are as much as twice as effective and may circumvent the drug resistance used by slippery tumors to evade Gleevec’s effects. “These two studies cap a remarkable decade of progress in CML therapy,” writes Charles Sawyers of Sloan-Kettering in an NEJM editorial.
If these successes sound somewhat small, you’re not wrong. In a New York Times article about the meeting, Charles Balch of Johns Hopkins described another set of promising ASCO results (for a melanoma treatment) as “a single, not a home run.” But as Gladwell wrote, the successes in fighting cancer are often of this incremental magnitude, with a glimmer of hope appearing in the narrow window between the lines of the Kaplan-Meier curve. A silver bullet cure for cancer is a fantasy, but moving the scoreboard against cancer along one productive single at a time offers a more realistic hope.