Lung Cancer Gene Discovery A Sign of Cancer's Future
Science is tackling gene-caused flaws, cancer stem cells, and earlier detection of tumors
The hoary metaphor of the war on cancer, as overused as it may be, is as evocative as ever to describe our efforts to beat the disease that will claim nearly 566,000 American lives this year alone. So let's fall back on martial imagery to describe our current position: We now know the enemy far better than ever before. And that promises much more precise targets.
Of course, as even Sun Tzu recognized, intel must be translated into effective action, and in this struggle, that effort has been all too plagued by failure. But mounting discoveries about the astoundingly complex essence of cancer—that its causes lie in multitudes of genes gone awry—are also pointing the way toward treatments aimed in laserlike fashion at a patient's unique set of genetic glitches. In mid-October, scientists reported in Nature that they've identified 26 key mutated genes linked to lung cancer, for example. "All of the pieces of the puzzle are in front of us," says Martin McMahon, a cancer biologist at the University of California-San Francisco Helen Diller Family Comprehensive Cancer Center. "It used to be that 10 percent of the pieces were in front of us and the other 90 percent were in a box under the stairs."
It's been clear for years, for example, that cancers vary widely even if they look the same under a microscope: Some are slow growing, others are aggressive; some patients respond to one drug, while others are not helped at all. Yet until quite recently, the only tools available—the blunt-force mainstays of surgery, chemotherapy, and radiation—treated everyone much the same. Then, in the 1990s, powerful new computing technology allowed researchers to begin comparing the DNA of cancerous and healthy tissues and gain a look at the very blueprints of similar-looking but markedly different tumors. Here's where the advances are leading:
Toward Personalized Treatment
Louise Cooper, an elementary school teacher and endurance athlete, is one early beneficiary. Now 55, she was diagnosed in 1998 with breast cancer and received the same basic knock-it-out treatment—surgery, chemo, radiation—prescribed for other women with similar-looking tumors. That's where Cooper's story diverged from the usual path: Her former neighbor is breast cancer expert Dennis Slamon, director of clinical and translational research at the University of California-Los Angeles Jonsson Comprehensive Cancer Center. Slamon and colleagues had discovered that in about a quarter of breast cancer patients, whose tumors were particularly aggressive, too many copies of a gene called HER2 within a cancer cell causes the overproduction of a certain protein on the cell surface that serves as a receptor for a growth-spurring substance. Cooper was tested at Slamon's suggestion and learned her tumor fit this description. "I found out that from diagnosis to demise, it's usually about two to three years, maximum," says Cooper, an L.A. transplant who grew up in South Africa.
But Slamon and his team had developed a drug that blocks the receptors, preventing the cell from getting the fix it needs to grow. After receiving weekly infusions of Herceptin for a year, Cooper is apparently cancer free—and off to Antarctica for a multiday 250-kilometer footrace just before Thanksgiving.
You might ask why Herceptin, now a weapon of choice in women whose tumors produce too much HER2, can't be used to block all sorts of cancer from growing. As science is revealing, there are thousands and thousands of mutated genes that contribute to cancer's uncontrolled growth and self-replication, refusal to die off, and ability to travel elsewhere in the body, lodge there, and thrive. As with HER2, a glitch might be found in some cancers in a particular organ but not others—and it may also be active in cancers in completely different organs. (HER2 is also associated with ovarian cancer.) In September, two research teams—one working on the government's massive new cancer gene-mapping initiative, the Cancer Genome Atlas project, and one on a separate private effort—described all the hundreds of possible mutations linked just to pancreatic cancer and a deadly form of brain cancer. The average pancreatic tumor, for example, included 63 mutations.
Devising treatments to combat every single mutation would be a huge task—but that may not be necessary, experts say. It seems that many of the aberrant genes operate together to create trouble in a smaller number of distinct cellular pathways—the molecular processes that make a cancer cell so deadly. "It has to grow faster, recruit a blood supply, and move around the body," notes Stephen Elledge, a geneticist at Harvard Medical School. These common pathways are the likely drug targets. Think of it this way: Multiple cars are taking separate routes to the same garage, and instead of trying to stop each car on the road, you block the driveway. The pathways are shared by cancers in different organs; the new lung cancer study, for example, revealed mutations also fingered in cancer of the retina and colon, among others, suggesting that drugs can be used against a panoply of tumors.
Within just a few years, the technology may be available to sequence an individual tumor's genes and find out exactly what pathways need blocking, says Raymond DuBois, provost of M.D. Anderson Cancer Center in Houston and president of the American Association for Cancer Research. Theoretically, that means drugs could be much better matched to patients. That kind of matching is only occasionally available now. Beyond Herceptin, Gleevec has proved very effective at blocking signals that encourage cell replication in certain leukemia patients with a specific chromosomal defect. Lung cancer drugs Tarceva and Iressa target the cell-growth receptor EGFR; for reasons not yet fully understood but most likely involving mutations in EGFR, they work better in some patients than in others.
Clearly, converting this mass of new genetic information into perfectly tailored therapies isn't a quick and dirty exercise. For one thing, finding all the mutations linked to a certain cancer isn't enough. "You have to separate the wheat from the chaff—some of those changes are driving the car, and others are just passengers," says Slamon. How and why are genes turned on and off? And how do the signaling pathways affect and influence each other? Even when a target is identified as important and a drug made to block it, chances are the tumor has another way to reach the same end—or will find one as it continues to grow and mutate, which explains why people develop resistance to targeted therapies that work at first. "Even as patients are responding, the tumors are trying to figure out a way to escape the block," says Neil Gibson, vice president of oncology research at Pfizer Inc.
What this all suggests, many say, is that just as HIV is now managed by a drug cocktail, cancer may one day be handled as a chronic disease controlled by a changing mix of several drugs at once in sequence or combination. The race is on to expand the arsenal. According to a recent Datamonitor report, 10 new targeted drugs have entered the marketplace since 2005, and researchers are studying existing therapies to see if they're more effective together. More are in the pipeline; Genentech and Roche, for example, are working on pertuzumab, which prevents the HER2 receptor from communicating with related receptors. There won't be one magic bullet, says Elledge. But "I absolutely believe we will be able to do this."
New Avenues of Exploration
While most doctors now talk in terms of managing cancer rather than curing it outright, there is one avenue of research—cancer stem cells—that might offer a permanent solution. Just as healthy adult stem cells in the body's organs produce cells for renewal and repair, the thinking goes, a small fraction of the cells in a single tumor manufacture tumor cells like little factories. Chemotherapy and radiation may seem to make a person cancer free when they actually leave the factories untouched to crank up production again later. Researchers have reported finding stem cells in leukemias and myelomas, as well as in breast, brain, pancreatic, and other tumors. Whether the cells are true stem cells or simply cells that have mutated to possess the stem-cell-like power of self-renewal is up for debate; either way, those properties are likely controlled by unique pathways that might be singled out and targeted.
It won't be easy to find and take aim at stem cells, since they're apt to look different from patient to patient, says Craig Jordan, a molecular biologist at the University of Rochester Medical Center whose lab is one of several working to develop new cancer stem cell treatments. But some drugs may already be blasting these cells. Gleevec may work so well because it eliminates leukemia stem cells, for example. And the breast cancer drug Tykerb appears to cut the number of breast cancer stem cells.
As well as explaining how a tumor recurs, some experts theorize that stem cells may offer clues to a cancer cell's deadliest function: metastasis. Perhaps the stem cells themselves stealthily leave the site of the original tumor and lodge elsewhere, sometimes hiding for years before beginning to grow again. Or perhaps they are capable of producing those highly mobile cells.
Understanding how cancer operates in the body requires looking beyond the cancer cell itself, at the tiny neighborhood of normal cells that surround it. Cancer that wants to grow and thrive has to recruit nearby cells to its cause, just as someone might borrow a cup of sugar from a neighbor. For example, the cascade of chemicals involved in the body's inflammatory response may help the cell invade healthy tissue, says David Cheresh, vice chair of pathology at Moores Cancer Center at the University of California-San Diego. And the various healthy surrounding tissues and cells play their part, too. One class of drugs, including Avastin for advanced colon, lung, and breast cancer, already buys some patients extra time by targeting one part of the tumor's outreach to its neighborhood: its recruitment of blood vessels to fuel its growth.
A friendly microenvironment is also key to metastasis. Ties between a cancer cell and its neighbors are already strong by the time a primary tumor grows, says Lynn Matrisian, chair of cancer biology at Vanderbilt University. But when a cancer cell travels to a distant organ, "in my mind, there's an opportunity to intervene" before neighborly relationships are cemented, says Matrisian. Indeed, drugs used to prevent osteoporosis can also make the bone less hospitable to metastatic cells from breast, prostate, and other cancers.
Metastasis might also be foiled by immunotherapy, which prompts the body's own defenses—usually muted or silenced by cancer—into action. At the Fred Hutchinson Cancer Research Center in Seattle, researchers reported in June that an experimental treatment involving the cloning of a patient's immune cells (and injection of a superdose) apparently sent one metastatic melanoma patient into remission. The treatment didn't have the same effect on several other patients. Johns Hopkins researchers are working on therapeutic vaccines against pancreatic and breast cancers.
Seeking the Earliest Signs
Of course, metastasis and the deaths that it causes could be avoided much more handily if more cancers were easily detectable early on, as are breast, colorectal, and a small handful of other cancers. "The [number of] cancer survivors is going up because we are catching things early, before they can spread," says geneticist George Miklos, whose Sydney-based consultancy advises companies on genetics and molecular medicine.
Jane Tervooren, now 55, believes early detection saved her life. She felt for years that she was destined to get cancer; her grandmother died of ovarian cancer, and her mother did too, after surviving breast cancer. "My mother made me swear, on her deathbed, that I'd get my ovaries removed," she remembers. She did that and registered with the Family Risk Assessment Program at the Fox Chase Cancer Center in Philadelphia, where she eventually discovered she carried an inherited mutation in a gene, BRCA1, associated with ovarian and breast cancer. Because of her heightened risk, she received preventive medication that blocks estrogen production and had her breasts monitored frequently. Earlier this year, a mammogram detected very early-stage cancer, and after surgery, she's being treated with chemo.
Tervooren had her ovaries removed because there is no proven method to detect cancer in that organ early. Ovarian cancer, like other cancers, is screaming for some kind of advance in early detection. And the search is on for "biomarkers"—DNA, RNA, or proteins in the blood and other bodily fluids that indicate the presence or progress of disease in the body. In fact, says Lee Hartwell, president and director of Fred Hutchinson, the hope is that these markers will not only point out cancer early but also help characterize it, reveal whether it's responding to therapy, and indicate whether a recurrence is likely.
Researchers at Fred Hutchinson are now investigating whether the body's immune response to the earliest presence of lung cancer can be detected in the blood, much the way an HIV test searches for antibodies to the virus. Other researchers have identified a potential protein biomarker for ovarian cancer called HE4, now in use to determine how far a tumor has advanced and being studied for screening.
The challenge is not so much finding markers as it is knowing what they mean. Don Listwin, founder and chair of the Canary Foundation, a nonprofit devoted to early-detection research, points out that markers aren't very useful unless they indicate only cancer and can distinguish the lethal types from ones that aren't likely to progress.
Prostate-specific antigen, or PSA, for example, can indicate the presence of prostate cancer. But it also leads to false alarms and detects slow-growing cancers that most likely would never have caused harm. Just this month, the Food and Drug Administration chastised the manufacturer of OvaSure for marketing—without approval—the new blood test that measures the level of six proteins associated with ovarian cancer. It's not definitive, and gynecologists worry that it will lead women to have unnecessary surgery to remove their ovaries. Canary has launched a clinical study to identify biomarkers that predict the more aggressive forms of prostate cancer and is also investigating early detection of lung, pancreatic, and ovarian cancers.
While researchers are optimistic, it's important to note that biomarkers have to be shown not just to find cancer early but to reduce mortality from the disease, says Beth Karlan, director of the Women's Cancer Research Institute at Cedars-Sinai Medical Center in Los Angeles and a member of the team that identified HE4. As history teaches, when it comes to cancer, there's good reason to temper optimism with caution. Fulfilling all this promise will take time, which won't please those who are tired of waiting. But "in 10 or 20 years," predicts M.D. Anderson's DuBois, "there will be a whole different way of detecting and treating cancer."
advertisement
