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NAUTILUS EDUCATION | BETA PRODUCT

patient (who doesn’t want her name made public) had such a wonderful response to everolimus, the technology was ripe to analyze her entire tumor.

The outlier patient had already gone through several rounds of treatment, including surgery at Memorial Sloan-Kettering. That was another stroke of luck because it allowed Solit’s group to acquire samples of her tissue to be sequenced. Cancers typically start with mutations that cause cells to divide too much, ignoring normal stop signals and evading quality controls that repair or prevent errors in DNA reproduction. “Cancer is a disease of mutations,” says Solit.

The outlier patient’s cancer had accumulated 17,136 mutations, of which 140 seemed most suspect, because they appeared in “coding” regions of the genome, the segments that include instructions on how to build the proteins that do the work in a cell. Out of those 140, two looked particularly menacing to Solit. In a gene called TSC1, just two of its 8,600 DNA base-pairs were missing, but the error would cause the gene to make a defective version of the protein it was supposed to create. In the gene NF2, an error meant a protein would be built only halfway, unable to do its job.

Solit could now see how these mutations were affected by everolimus, a drug typically used to suppress the immune system after organ transplants, and to combat advanced kidney cancer. Everolimus shuts down one crucial link in a chain of interacting proteins called the mTOR pathway that fuels cell growth, division, and survival. The drug inhibits the cells of the immune system from dividing, which they must do in order to attack foreign tissue, and protects transplanted organs. Likewise, it slows down the uncontrolled cell division that happens in cancer. The kicker was that both of the woman’s mutations, NF2 and TSC1, affect the mTOR system. “It’s not surprising, in retrospect, that our patient responded really well to this specific drug,” Solit says. “She had the mutation that activated the pathway the drug targets.”

Solit’s team analyzed 13 more people from the trial and found different TSC1 mutations in three other people, including two whose tumor shrank a little in response to the drug. (Nobody else had NF2 mutations, which is probably why she alone responded dramatically.) Meanwhile, eight of nine people whose tumors grew during the study did not have the mutation.

DOROSHOW OF THE National Cancer Institute says Solit’s work “turned on the lightbulb.” It showed how the analysis of exceptional responders could be made systematic. Inspired by his example, the NCI is now trawling through its own archives, revisiting outlier responses among the roughly 10,000 patients who enrolled in NCI-sponsored clinical trials during the last decade. Picture the long rows of crates in the government warehouse at the end of Raiders of the Lost Ark: There’s treasure in there somewhere, if only someone would look. “We ought to study these people more, since we have the means now,” says Barbara Conley, the associate director of the cancer diagnosis program at NCI, who leads the project.

In the few months since the project began, Conley’s team have already found about 100 exceptional responders. The next steps are to find out if their tumors were biopsied, if that tissue sample is still sitting in a freezer somewhere, and whether it’s in good enough shape to be sequenced. Starting next year, the group will start inviting any scientist who is doing a clinical trial to submit new cases.

The NCI project will include whole-genome sequencing (provided they have adequate tissue samples) and repeated reads of the whole “exome”—the 1 percent of human DNA that is translated into exons, the sequences that are used as templates for protein construction. The reason to do both, explains Conley, is that cancer cells, even within a single tumor, often have a hodgepodge of mutations. Re-doing whole exome sequencing dozens of times captures most of the significant genetic variation in one tumor, and it’s more practical than trying to sequence the whole genome over and over. Finally, RNA expression will also be analyzed. Evaluating RNA, an intermediary between DNA and proteins, provides a measure of which genes are switched on and how much protein they’re producing.

Other elite cancer research centers and genome-sequencing centers have similar in-house projects. Much like the NCI project, the unusual responder program at the University of Texas, MD Anderson Cancer Center, is beginning by combing through the archives to hunt for outliers of the past. A patient at the clinic who has an unusual response—good or bad—will also be referred for genome sequencing and other kinds of genetic analysis.

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