Across the Expanding Universe
To get a handle on the state of cancer research today, you have to think big. Really big. Astronomically BIG.
“Biology is more complicated than great swaths of the universe,” says Michael Freeman, PhD, director of the Cancer Biology Program at Cedars-Sinai’s Samuel Oschin Comprehensive Cancer Institute. “The chemistry of a star is pretty simple. But if you look at a single cell, it’s a complex organism.” And a tumor is a shape-shifting colony, one that displays an adaptive intelligence that continues to outsmart us in clinics and laboratories around the world.
Since President Richard Nixon launched the War on Cancer 41 years ago, battles have been fought and won. People are living longer and better with the disease, and some common forms have been eradicated. Targeted therapies, therapeutic vaccines, and improved imaging and screening technologies all give patients additional months and years of life. We are gaining ground.
Still, major victories are elusive, and the diagnosis is commonly received as tragic. Even if a winning therapy is found for a patient, it may fail after a year, or three, or 10. When the word “cure” is used, it is often accompanied by scare quotes and a wistful tone. About half of adults with cancer will eventually die from their disease. It makes Robert Figlin, MD, question whether the War on Cancer remains a relevant concept. “A war has a beginning, a middle, and an end,” says Cedars-Sinai’s director of Hematology/Oncology. “This war is longer than Vietnam, it’s longer than Iraq, it’s longer than World War II, and there are many more casualties.”
The long trudge of the not-war-on-cancer finally has arrived at a turning point. Excavating the human genome has thrown light onto the depths of the disease. Vulnerability does not lie in a single cell, gene, or mutation. Enlightenment and new technology have encouraged scientists to flip an old research paradigm on its head. Dr. Freeman, the cancer biologist, would say we are attacking the cancer universe as a whole instead of one star at a time, raising the possibility of novel treatments that endure. Whether the new approach brings us closer to a cure—and what that even means—is an open question.
The crux of the cancer problem is that the disease is, by its very nature, diverse. “Cancer is a single word, but it’s a disease of many types,” notes Dr. Figlin. The American Cancer Society lists 71 types on its website. Genetic research is revealing that many subtypes exist within simple descriptors such as “lung cancer” or “breast cancer.” Physicians leading the field have realized that categorizing cancers by body part does not work very well anymore.
“I think we need to begin taking an ‘organ-agnostic’ approach,” says Beth Y. Karlan, MD, director of the Women’s Cancer Program at the Samuel Oschin Comprehensive Cancer Institute. “No longer should we be thinking, ‘This is an ovarian, colon, prostate, or breast cancer.’ The question is which combination of genetic mutation and/or cellular action drives an individual patient’s tumor.” To make matters even stickier, a single patient’s tumor can contain cells with different genetic makeups. “Our individualized treatments need to be directed at those specific molecular differences.”
“There is a legion of enemies,” says Dr. Karlan, who has been on the front lines for almost three decades. “I’ve pondered this for years. I can do two identical surgeries on two women with the same cancer on the same day but have different outcomes. I remove all their tumors, and I feel really good about it—yet flash forward and one is dying at two years, and one is alive at 20. No two people have the same disease.”
All cancers start the same way: An abnormal cell grows out of control. Over the last two decades, the most promising research into cancer therapies has relied on targeting: Find the mutated gene that turns a normal cell into a malignant one, identify the “problem” molecule, and develop a drug that prevents the cancer from growing. “With a targeted drug, we might help 3 percent of lung cancer patients who have a known mutation and, for that 3 percent, it’s a home run,” says Dr. Figlin. But what about the other 97 percent, or the patient for whom a therapy simply quits working?
According to Dr. Freeman, the trouble lies in a reductionist research approach. “The problem molecule doesn’t exist in isolation,” he explains. “It interacts with thousands of other molecules—and so does the drug.” Each cell lives in a multi-layered environment, an intricately woven network threaded with feedback loops. The tumor cell ultimately adapts to treatment, and the drug stops working. “It’s like the Borg,” Dr. Freeman says, referencing the powerful cybernetic race of humanoids from the world of Star Trek. “You kill one and you kill another one, but by the time you get to the third one, they’ve got your number.”
Dr. Freeman is a practitioner of a revolutionary scientific movement called systems biology. It’s a burgeoning branch of biology that uses powerful computational tools to evaluate massive amounts of molecular, cellular, and genetic data. “Systems biology is like astronomy where you build more and more tools to get better and better data and eventually you understand the structure of the universe,” explains Dr. Freeman. “The philosophy is that if you cast the net really widely, you will find things about cancer you never would have found if you did experiments in a traditional way, looking at one little part of the organism.” It is the antithesis of reductionism.
The Human Genome Project was the moonshot that propelled systems biology. Completed in 2003, the international effort resulted in a genetic blueprint for Homo sapiens and fueled the discovery of 1,800 disease genes. The project opened a wormhole to an entirely new view of biology and, as Dr. Figlin points out, “If you don’t understand the biology of what’s going on in the tumor, you can never cure it.”
Systems biology and cancer research take personalized medicine to the extreme. “If Mrs. Smith comes in today with colon cancer, it’s a story about colon cancer. In the future, it could be the story of Mrs. Smith and her colon cancer,” explains Dr. Figlin. In that story, Mrs. Smith’s doctors understand the intricacies of her genome and the inner workings of her tumor. A team of physicians and scientists examine her family history, immune system, and tumor microenvironment. And, because researchers have analyzed huge numbers of tumors just like Mrs. Smith’s, her doctors can provide tailored therapy. They know whether she needs aggressive treatment, or if her cancer just needs to be watched. They can deliver the perfect drug at precisely the right time.
“We are attacking the cancer universe as a whole instead of one star at a time, raising the possibility of novel treatments that stick.”
It will take time for reality to catch up to that dream. Scientists are developing a deeper subclassification system for cancers, and genomic studies continue to offer new pieces of the puzzle. However, “We are realizing this isn’t a 1,000-piece puzzle,” says Dr. Karlan, who leads studies on the genetics of breast and ovarian cancers. “It’s a 10,000-piece puzzle. We may have the perimeter laid out, but we don’t even know what the picture looks like yet.”
“I worry that our expectations and technology are outpacing reality,” adds Dr. Figlin. Physicians do not yet have the capacity to interpret all the information available and translate it into treatments.
Dr. Freeman agrees that the medical community needs to be careful not to over-promise and under-deliver. “In the astronomy example, we have advanced from looking at the universe through Galileo’s telescope to using the Hubble telescope. The high-throughput computational tools we have now are going to give us a lot of information. But will that lead to a complete cure?” That question lingers, unanswered.
What would a cure for cancer look like? Is it a rational goal for such a wildly diverse disease? Many diseases, from tuberculosis to AIDS, represent an invasion by an “other.” Cancer is bizarrely personal, as each of us carries the potential within each cell.
“We could sequence your genome for a few thousand dollars right now, and what would we find there?” says Dr. Freeman. “All of us have genomic damage. You’re going to find mutations in important genes. You might have one that creates a high risk factor for cancer.” Can you cure something that roots in your every cell? A commonly offered trope is that in a world with a cure patients don’t die of cancer, they die with cancer. For the lifetime of the patient, the cancer is controlled like other chronic diseases, so the patient may die of something else.
“That’s the right goal, but I don’t call it a cure,” argues Dr. Figlin. We do not, after all, ask endocrinologists to cure us of diabetes. We talk about controlling risk factors and managing symptoms. “Cancer has been carved out as a different dialogue from that surrounding diabetes or heart disease because it is so tragic, and it is an acute disease,” explains Dr. Figlin. “But for the person with cancer, at the end of the day, he or she wants to live a happy and fruitful life, and we should aim to deliver this. Maybe we shouldn’t be so hung up on this ‘cure.’” Maybe like “winning the war,” it is an outdated concept for a simpler time.
As complex as cancer is, researchers tend to agree that the disease does not present an infinite problem.
“Historically, tumors tend to outsmart science,” warns Dr. Freeman. “We have a lot of promising treatments today— personalized medicine and genomics—but chemotherapeutic drugs looked similarly promising in the 1970s.”
Despite being a natural skeptic, the systems biologist views cancer’s new research path with optimism. “I think that at some point in the future, this will work,” he says. “With all the technology coming online, you can imagine that, in 50 years or less, we might have some Star Trek-like scanning device and—boop—you’re cured, you can go home now!”
Dr. Figlin tends to agree that the disease does not present an infinite problem. “Thirty years ago, I was talking to patients about managing death. Now I talk about managing the disease,” he says. “I have no doubt that 30 years from now, we will look back and marvel at how far we have come.”