The Cancer Chronicles Read online

  Outside the laboratory enthusiasm for this scenario is driven both by hope and by fear. Epigenetics might provide a way for a substance to act as a carcinogen even though it has been shown incapable of breaking DNA. But unlike genetic damage, these changes might be reversible. How big a role epigenetics plays remains uncertain. Like everything that happens in a cell, methylation and the modification of histones are controlled by genes—and these have been found to be mutated in different cancers. Maybe it all comes down to mutations after all. On the other hand, a few scientists have proposed that cancer actually begins with epigenetic disruptions, setting the stage for more wrenching transformations.

  Even more unsettling is a contentious idea called the cancer stem cell theory. In a developing embryo, stem cells are those with the ability to renew themselves indefinitely—they are essentially immortal—dividing and dividing while remaining in an undifferentiated state. They are agents of pure potentiality. When a certain type of tissue is needed, genes are activated in a specific pattern and the stem cells give rise to specialized cells with fixed identities. Once the embryo has grown into a creature, adult stem cells play a similar role, standing ready to differentiate and replace cells that have been damaged or reached the end of their life. Since healthy tissues arise from a small set of these powerful forebears, why couldn’t the same be true for some tumors?

  This would be an unexpected twist on the conventional view in which any cancer cell that has acquired the right combination of mutations is capable of generating a new tumor. Imagine if instead the growth and spread of a cancer is driven by a fraction of special cells, those that have somehow become endowed with an intrinsic quality called “stemness.” Just as normal stem cells generate skin, bone, and other tissues, the cancer stem cells would generate the variety of cells that form the rest of a tumor. But only the cancer stem cells would have the ability to replicate endlessly, metastasize, and seed another malignancy. How much easier that might make things for oncologists. Maybe chemotherapies fail because they spare the cancer stem cells. Remove these linchpins and the malignancy would collapse.

  It is a promising possibility, but the further I ventured into the subject, the more confusing it seemed. Do the other cells in the tumor perform functions like angiogenesis that would aid in sustaining the malignancy? Or are they just filler material? And where would the cancer stem cells come from? Do they begin as normal stem cells (like those that generate skin) that become damaged by mutations? Or are they fetal stem cells that survived into adulthood and then went berserk? Or, like the other cells jostling for position inside a tumor, did they also arise through random variation and selection? Maybe the all-powerful cells began as “ordinary” tumor cells that shed their identity and reverted to this primal form. Some experiments suggest that in the turmoil of a tumor, cells are constantly shifting their identity between cells with stemlike properties and cells without.

  As I struggled to fit this all into the big picture, I was relieved to find researchers who seemed as baffled as I was. Some scientists were convinced the hypothesis was the wave of the future, others that it was of limited importance—a footnote to the standard theory. However it all pans out, the underlying view of cancer as a Darwinian process—arising like life itself through random variation and selection—would remain largely unshaken. But as an outsider trying to understand the essence of cancer, I felt daunted by the possibility of even more convolutions.

  The place to take in the full sweep of what is happening on the frontiers is the annual meeting of the American Association for Cancer Research, the largest and most important of its kind in the world. It was being held early one spring in Orlando, Florida, and as I changed planes in Atlanta I could already see the ripple effect. Young scientists rushed through the airport carrying long cardboard tubes protecting their posters. Each, unfurled, would describe a tiny piece in the expanding puzzle. Altogether more than 16,000 scientists and other specialists from sixty-seven countries were converging on Orlando, where more than six thousand new papers would be presented—in poster sessions and symposiums—over a span of five days. There were few distractions. Orlando’s mammoth convention center and its environs form an insular world of hotels, chain restaurants, and meeting halls, a kind of boring version of Las Vegas. Inside this air-conditioned bubble I hoped to absorb as much as I could.

  While there had been three simultaneous sessions at the modest developmental biology meeting I had attended in Albuquerque, here there were more than a dozen—beginning at 7:00 a.m. and running into the evening with major lectures and educational sessions overlapping and in between. Carrying a copy of the proceedings as thick as a telephone book (or the weightless equivalent on their cell phones), the informavores plotted their hunting strategies. As the clock began to run out on a speaker’s 10:30 a.m. talk, there would come a rustling of chairs with people quietly hurrying to a presentation scheduled in another room for 10:45. Geography was a consideration. Going from “Guts, Germs and Genes” (recent findings on the role bacteria play in the onset of some tumors) to catch the end of “Ubiquitin Signaling Networks in Cancer” required a brisk ten-minute walk indoors. Beckoning one floor below was the exhibit area, where pharmaceutical companies with huge steampunk espresso machines tempted passersby—a cappuccino and biscotti in return for listening to a presentation by Merck or Lilly on a new cancer drug. At the Amgen booth, visitors wearing 3-D glasses watched an amazing video flythrough of a tumor undergoing angiogenesis. For more than a decade Amgen had been working on an angiogenesis inhibitor. Combined with paclitaxel in a clinical trial, it extended the lives of women with recurrent ovarian cancer from 20.9 months to 22.5 months, or about forty-eight days.

  As I watched the video, I thought of the excitement thirteen years earlier when a Harvard scientist, Judah Folkman, had discovered what briefly appeared to be the makings of a silver bullet. For every mechanism in a cell there is a countermechanism to keep it in check. Angiogenesis is a normal means through which blood is supplied to newly created tissues. Molecules called angiostatin and endostatin, which are naturally produced to inhibit angiogenesis—you don’t want new blood vessels growing just anywhere—had shown striking effects in choking off tumors in mice. James Watson, the celebrated molecular biologist, was quoted on the front page of The New York Times: “Judah is going to cure cancer in two years.” He followed up with a letter to the editor insisting that he had spoken more cautiously to the reporter—and then went on to declare, just as enthusiastically, that what was happening in Folkman’s laboratory was “the most exciting cancer research of my lifetime, and it gives us hope that a world without cancer may yet be attainable.” Watson was not alone. The director of the National Cancer Institute called Folkman’s results “remarkable and wonderful” and “the single most exciting thing on the horizon,” before adding the usual caveat that what worked for mice wouldn’t necessarily work for people.

  It didn’t, of course. The experiments were difficult to replicate and later research suggested that some angiogenesis inhibitors might make matters worse—with the tumor fighting back by metastasizing more vigorously toward safer ground. There are now inhibitors on the market, but the results are nothing like what had been envisioned. Used along with the standard blunt-edged poisons, Avastin can add a few months to a patient’s life at a cost of tens of thousands of dollars. Side effects include gastrointestinal perforation and severe internal bleeding. Inhibiting angiogenesis can interfere with the healing of surgical incisions and other wounds. Several months after the Orlando meeting, the Food and Drug Administration, weighing the risks and the benefits, revoked approval for Avastin as a treatment for metastatic breast cancer.

  Such grim realities seemed far away at the grand opening session, where Arthur D. Levinson, a pioneer in the design of targeted therapies, was honored for “leadership and extraordinary achievements in cancer research.” He was cited specifically for his role in developing “blockbuster drugs” like Avastin. Levinson is the chairm
an of Genentech, which also makes Herceptin to treat the 15 to 20 percent of breast cancers that are HER2 positive—those with an overabundance of the growth-stimulating receptors. For metastatic breast cancer, Herceptin can add a few months to a woman’s life. Used in the early stages of the illness, the drug’s effects are more striking. When standard chemotherapy was accompanied by Herceptin, 85 percent of women were found free of the cancer after four years. That compared with 67 percent who had not taken the drug. The trial was stopped early so that women in the control group could benefit (and so Genentech could reduce the time to market). As word spread of the new therapy, breast cancer patients who once dreaded learning that their tumor was HER2 positive—a particularly vicious and aggressive kind—came almost to welcome the news.

  No cancer drug, however, is as good as it sounds. Herceptin can also affect healthy cells with a normal number of HER2 receptors, and there is a serious risk of congestive heart failure. Even Gleevec, the “crowning achievement” of targeted therapy, has its dark side. With the drug, chronic myeloid leukemia can almost always be held in check, but Gleevec must be taken indefinitely to keep the cancer from coming back. There are also problems with another class of pharmaceuticals that aim to suppress tumors by strengthening the body’s immunological defenses. Immune system boosters called cytokines are infused into the bloodstream—or the patient’s own immune cells are removed, modified to enhance their killing powers, and then reinjected. The danger with these experimental therapies is keeping the immune system from becoming so vigilant that it wildly overreacts, mistaking the body itself for an interloper and initiating a catastrophic autoimmune response.

  As I pondered what counts as a blockbuster drug, the auditorium was aroused by a fanfare of strings. This was a first for me—a scientific meeting with its own musical theme. Harold Varmus, the director of the National Cancer Institute, was taking the stage. To accommodate an audience of thousands of people, each speaker’s image was projected on six sets of double screens—one half for the video of the lectern and the other for PowerPoint slides. The images loomed so large that the speaker himself, off in the distance, appeared comically small, the man behind the curtain in The Wizard of Oz. Varmus began with the good news: Overall incidence and mortality rates were continuing to inch a little lower every year. That, of course, is after adjusting for the aging of the population. The frightening reality, he reminded everyone, is that wave after wave of baby boomers are entering their sixties and seventies—prime cancer time. Even with a modest decline in the amount of cancer per capita, the sheer number of cases will soar. At the same time government research funding was not even keeping up with inflation. “We’re not just poor but living in a land of uncertainty,” Varmus lamented.

  Watching these lavish presentations with their state-of-the-art audiovisual enhancements, I found it hard to think of cancer as medicine’s neglected stepchild. All medical research has been threatened by budget cuts. But when you add to the government grants the money that is going toward pharmaceutical research (the justification given for those five-figure drug price tags) and the private dollars raised in telethons and donated by the wealthy hoping to stave off their own death or to memorialize a loved one with a new medical center wing, great resources were going toward understanding cancer in the minutest detail. Would billions of additional dollars soon lead to the drugs, always just beyond the horizon, that would zero in on advanced-stage cancer without the collateral damage of chemo and radiation, buying not just weeks or months but an actual cure? Would death rates fall as precipitously as they have for heart disease? Would people stop lamenting that we are losing the War on Cancer?

  There is so much money to be made in the fight, and I was taken aback by how many top university researchers had a hand in the commercial world. Elizabeth Blackburn, who was stepping down as president of AACR, had won a Nobel Prize for her research on telomeres and telomerase. She was also a founder and chairman of the advisory board of an enterprise called Telome Health, Inc. Throughout the week every presentation began with an obligatory slide disclosing any conflicts of interest. There was clearly some resentment over the requirement. Some speakers flashed the words so quickly that they were impossible to read. I was reminded of those television car commercials where a comically sped up voice rapidly spews out the fine print and disclaimers. One plenary speaker hurriedly said that she had lost her slide. (It would have indicated that she and her husband were cofounders of a publicly traded pharmaceutical company that is developing targeted cancer therapies.) Other speakers proudly declared, often to applause, that they had nothing to disclose, and one said that his biggest conflict of interest was that for twenty-five years he had worked on a skin cancer treatment “and therefore I really want this stuff to work.”

  Varmus is one of the giants of medical science, sharing his own Nobel Prize with J. Michael Bishop for their pioneering work on viruses and oncogenes. He seemed glad to get money matters out of the way so he could move on to the science and some of the most perplexing questions it faced: Why is it that some cancers—testicular, for example, and some leukemias and lymphomas—can be killed by chemo alone while others are stubbornly resistant? What are the biological mechanisms that account for obese people having a higher cancer risk? Why do patients with neurodegenerative diseases like Parkinson’s, Huntington’s, Alzheimer’s, and fragile X appear to be at lower risk for most cancers? Why do the body’s tissues differ so dramatically in their tendency to develop cancer? As I listened, it occurred to me that I had never heard of cancer of the heart. (It does occur but is extremely rare.)

  For the rest of the morning other luminaries stepped forth to speak about the future, each preceded by the rousing melodic fanfare and the disclaimer slide. With the latest technology researchers are sequencing the genomes of cancer cells, far more rapidly than had seemed possible even a few years ago. By comparing the tumor genomes with those of normal cells, they are seeing on a finer grain than ever the mutations that can produce a malignancy. Some of the results have been surprising. According to the common wisdom it typically takes half a dozen or so damaged genes to tip a cell. But two cases of the same kind of cancer (breast cancer, say, or colon cancer) needn’t arise through the same combination of genetic alterations. Genomics research suggests that for some cancers dozens and even hundreds of mutations may potentially be involved. Of the approximately 25,000 genes in the human genome, at least 350 have been identified as possible cancer genes—ones that can be altered in a way that confers a competitive advantage. According to some predictions, the number may eventually run into the thousands.

  “Cancer is not a disease. It’s a hundred different diseases”—how many times has that been said? Now the talk is of cancer as tens of thousands of diseases each with its own molecular signature. One day, as these technologies develop, scientists may be able to routinely analyze the unique characteristics of every individual cancer and provide each patient with a personally crafted therapy. It is a lot to hope for.

  We left the auditorium, the thousands of us, and diffused throughout the cavernous spaces of the convention center. Every lecture room and every corridor of posters offered more elaborations on the cancer theme. There was the phenomenon of polarization—the way a healthy cell can tell its front from its back. This allows epithelial cells to orient themselves within a tissue so that hair, scales, and feathers all lean the same way. During mitosis a cell must polarize, portioning out its contents before it splits into two identical cells. A migrating cell is exhibiting polarization when it transports its proteins in a way that keeps it moving forward and not backward, as though riding on its own conveyor belt. Some of the molecular circuits involved in polarization have been uncovered, and in a cancer cell they are among the things that can go askew. Whether that is a symptom or a cause of the malignancy is another of the unknowns.

  While that question was being pondered, researchers in another room were discussing the many different kinds of cell death. Switching off
apoptosis is an established hallmark of cancer, and chemotherapy typically works by forcing apoptosis back on. But there are also autophagy (the cell eats its own insides), entosis (a cell cannibalizes its neighbor), and necroptosis, which like apoptosis involves molecules called death receptors and RIPs (the epitaph stands for “receptor-interacting protein”). Maybe these too can be manipulated in controlling cancer. There is a Journal of Cell Death, and a woman in the audience was wearing a black T-shirt with the cryptic words “Cell Death 2009: The Unplugged Tour.” So many little subcultures even in the cancer world.

  Other speakers pondered the mystery of why cancer cells change their metabolism from aerobic to anaerobic, voraciously consuming glucose in a phenomenon called the Warburg effect. This less efficient way to use energy would help them survive in the oxygen-starved reaches deep inside a tumor. But the cells also make this transformation when there is plenty of oxygen available. One reason might be that the altered metabolism allows them to take in more of the raw material they need to build new parts and proliferate. There were lectures on the ways in which a cancer cell can elude destruction by the immune system—or turn it to its own uses, attracting macrophages as allies in the cause. The slow burn of chronic inflammation is somehow involved with many diseases—rheumatoid arthritis, Crohn’s disease, Alzheimer’s, obesity, diabetes—and it also plays a role in cancer. Stomachs inflamed by an immune response to Helicobacter pylori bacteria or livers inflamed by hepatitis virus are more likely to become cancerous. But how much is cause and how much is effect? The chemical circuitry is still being uncovered. A full session was devoted to the question of how molecules called sirtuins, which have been implicated in the aging process, also play a role in inflammation, obesity, and therefore in cancer.