At the 2011 meeting of the American Society of Clinical Oncology (ASCO), outgoing president George Sledge told the audience that while drug developers were becoming smarter than "stupid cancers" cancers defined and driven largely by a single mutation that could be attacked with targeted therapies they needed to become smarter than "smart cancers" that are characterized by an overall high mutational load and will quickly mutate their way around any targeted therapy. (See BioWorld Today, June 13, 2011.)
By that definition, lung cancers, especially those in smokers, are the Ivy Leaguers of cancers. Sledge said at the 2011 ASCO meeting that by some estimates, smokers get one mutation for every three cigarettes they smoke.
A slew of papers in recent weeks are a sign that scientists are making inroads into those smart tumors. Last week, a study in the Sept 9, 2012, issue of Nature reported on the genetic landscape of squamous cell carcinoma; one paper in the Sept 13, 2012, issue of Cell compared non-small-cell lung cancer in smokers and never-smokers; and another paper looked at adenocarcinoma, which is the most frequent subtype of non-small-cell lung cancer. Those papers followed two other papers in the Sept. 2, 2012, issue of Nature Genetics that had reported on the genomics of small-cell lung cancer.
The studies, Ramaswamy Govindan, of Washington University in St. Louis, told BioWorld Today, "provide, for the first time, a window onto the genomic landscape rather than a view through a keyhole." And "through these exercises, we will be uncovering a lot of pathways that we hadn't really been paying much attention to."
Govindan, who is the first author of the paper comparing smoker and nonsmoker tumor genomes and is also involved with the Cancer Genome Atlas, which published two of the other papers, likened the situation to former defense secretary Donald Rumsfeld's description of known unknowns and unknown unknowns in foreign policy.
Of course, becoming aware of the unknown unknowns can be a daunting experience. With the number of mutations his team found in the tumor genomes of smokers, finding the needle in the haystack that is a given tumor's driver mutation "becomes that much more complicated," Govindan said.
He said that in his opinion, the results of the work that he and his colleagues published in Cell and Nature make three critical points.
First, perhaps unsurprisingly given the mutagenic power of cigarettes, "the genomes of never-smokers are much less deranged than the genomes of smokers."
The studies also pointed to changes in epigenetic mechanisms, such as genes involved in chromatin regulation, as important in lung cancer.
And finally, he said, the papers, for all their bewildering complexity, had a hopeful bottom line. "Every nonsmoker had a targetable mutation."
The development of new therapeutics based on the data is a good while off at best. In his 2011 talk at ASCO, George Sledge noted that another way to describe smart cancers is that they are chaotic. Alas, the clinical trial system "is not designed for chaos."
But, Govindan said, on an individual level, "clinical advances based on these data are already happening," as clinicians use information from genome sequencing to assign therapeutics to patients. In their paper, which looked at 17 patients, he and his team identified more than 50 druggable targets.
For now, it is only patients in clinical trials who can take advantage of such cutting-edge possibilities. But access is sure to become more widespread, driven by advances in genome sequencing Govindan said that "massive parallel sequencing has become easy to do" that have to do with the sequencing itself, but also with how much tissue is needed for such sequencing.
One obstacle to the sequencing of small-cell lung cancer reported in Nature Genetics was simply getting enough tissue to do it, as this tumor type is not often treatable through surgery. But, he said, "increasingly, we will be able to do needle biopsies" to get tissue, doing away with the need for fresh-frozen tumor samples from surgeries.