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Not long ago, the task of linking a mutated gene to cancer could consume the better part of a scientist's career. Today, it may take as long as a week. Advanced DNA-sequencing technology can speedily deliver lists of the mutations within a set of tumor cells–the various misspellings, duplications, and garblings of the genetic code that can send cell growth into overdrive. And impressive lists they can be. If the cancer being scanned is a lymphoma or leukemia, the number of mutations may be less than a dozen. If it's a lung cancer or melanoma, the figure is apt to be in the hundreds, if not thousands.
The challenge for scientists, then, has shifted from one of scarcity to surplus. In tumor cells with, say, 1,000 mutations, the number of mutations actually driving the cells' growth and survival may be relatively small (though no one knows how small). The remainder of the mutations, regardless of where or why they arose, have little influence on the tumor's behavior and are, essentially, along for the ride – hence their name, "passenger" mutations. When designing new cancer drugs, investigators clearly want to aim at the mutations responsible for cancer cells' chaotic growth. The question then becomes how to distinguish drivers from passengers, the legitimate targets from the decoys. The mutations themselves offer few clues: a typo in a single letter of DNA can sometimes wreak havoc; a gene copied multiple times over may have no negative impact.
"For lung cancer and many other cancers, we're drinking from a firehose, trying to select out the few gene mutations that matter amid the torrent of mutations that are less critical," says Kwok-Kin Wong, MD, PhD, scientific co-director of the Belfer Institute for Applied Cancer Science at Dana-Farber, which seeks to discover new treatments by understanding the mutations that make cancer go.
Getting a bead on driver mutations wasn't difficult initially. "There are a number of mutated genes that have been known for 20-25 years to be involved in cancer – genes such as ras, BCR/ABL, and Myc," says William Hahn, MD, PhD, Dana-Farber's deputy scientific director and director of the Institute's Center for Cancer Genome Discovery. "The problem was that, other than these, we knew very little about which genes underlie different types of cancer."
Researchers began by focusing on the mutations most clearly connected to cancer. Scientists knew that enzymes known as kinases are often abnormal in cancer cells. So it was natural for kinase genes to be among the first considered as drivers.
Another clue was how often a particular gene is found to be mutated in cancer. "If it happens at a highenough frequency – if it occurs in, say, 30 percent of cancers of a certain type – we'll be pretty suspicious that it plays an important role," Hahn remarks.
"Researchers initially looked at the genes that had been extensively studied and described," Wong says. "From that base of knowledge, you start building a picture of how they contribute to cancer. If you're interested in a gene about which little is known, you have to build that biological understanding yourself. That is what the Belfer Institute and other labs at Dana-Farber are doing."
The challenge of identifying the drivers goes beyond finding which mutations are troublemakers in laboratory specimens of cancer cells. Tumors are best understood within their natural surroundings, the layers of normal and near-normal tissue that enfold them within the body. A group of gene mutations that causes cell reproduction to go berserk in petri dishes may have an entirely different effect – or no effect – in actual organs and tissues. Laboratory techniques that simulate the living environment of tumors are critical to this research.
"When we look for driver mutations, we need to take into account all the different types of cells that are around the tumor, that feed the tumor and promote its growth," says Jesse English, PhD, the Belfer Institute's head of research. "We've developed several strategies for studying the effect of mutations within the context of a tumor's normal environment."
Belfer Institute researchers use two main approaches – or platforms – to cull driver mutations from the throng of passengers. The first is contextspecific screening (CSS). English explains: "In any given tumor type, there are often baseline mutations – a small group of mutations that don't necessarily make a cell cancerous, but start it in that direction. The question is, which additional mutations will push the cell over the edge into cancer?"
Belfer Institute scientists have created such almost-cancer cells for a variety of tumor types. They slip suspected driver mutations into the cells' DNA and implant the cells in lab animals, in the same tissue where such cells might naturally be found. If the cells become cancerous, it's an indication that the added mutations are indeed drivers.
The second strategy is a "depletion screen" involving shRNA (the "sh" stands for "short hairpin" but might just as well stand for "Shhh!" as the technique involves silencing genes one at a time). "We use viruses to carry shRNA into laboratory samples of tumor cells," explains Belfer Institute scientist Mark Bittinger.
"The RNA shuts down a specific gene, and we track whether the cells stop growing and die. It's a systematic way of determining whether a particular gene is necessary for tumor cell survival and proliferation. "This approach, known as RNA interference, mimics the way a drug against an individual gene would work. It has become the workhorse of efforts to discover cancer-related genes that make good targets for new therapies."
Hahn and his colleagues have harnessed RNA interference in an effort dubbed Project Achilles. Named after the mythical Trojan War hero who was killed by a wound to the weak spot in his heel, the project is concerned with vulnerabilities, specifically the genes on which cancer cells depend for their growth and survival.
"We're screening at least 500 cancer cells lines in which we know all of the genetic alterations and asking, if we turn off those genes one by one, can we identify which are critical? It's our hope that the project will result in a global picture of how to find those vulnerabilities," Hahn comments. "We're about halfway through the project [which began in 2010], but it's already enabled us to begin exploring the links between certain mutations and cell survival."
Hahn and other scientists emphasize that no single approach – whether in laboratory cell cultures, tumor tissue samples, or animal studies – will be sufficient to decisively label a particular gene mutation as a driver. Rather, it will require a combination of these approaches to identify the most likely offenders.
Also, driver mutations rarely work solo. In the vast majority of cancers, it isn't one mutation but a combination of them that are responsible for turning a cell cancerous and keeping it that way. Researchers are hard at work trying to determine which combination of mutations provides the formula for cancer, and which combination of therapies can undo the damage those mutations have produced.
Paths of Progress Spring/Summer 2013 Table of Contents