The Best American Science and Nature Writing 2011 (28 page)

The first patient treated under the experimental regimen was a young girl. Freireich started her off with a dose that turned out to be too high, and she almost died. She was put on antibiotics and a respirator. Freireich saw her eight times a day, sitting at her bedside. She pulled through the chemo-induced crisis, only to die later of an infection. But Freireich was learning. He tinkered with his protocol and started again, with Patient No. 2. Her name was Janice. She was fifteen, and her recovery was nothing short of miraculous. So was the recovery of the next patient and the next and the next, until nearly every child was in remission, without need of antibiotics or transfusions. In 1965 Frei and Freireich published one of the most famous articles in the history of oncology, "Progress and Perspective in the Chemotherapy of Acute Leukemia," in
Advances in Chemotherapy.
Almost three decades later, a perfectly healthy Janice graced the cover of the journal
Cancer Research.

What happened with ALL was a formative experience for an entire generation of cancer fighters. VAMP proved that medicine didn't need a magic bullet—a superdrug that could stop all cancer in its tracks. A drug that worked a little bit could be combined with another that worked a little bit and another that worked a little bit, and, as long as all three worked in different ways and had different side effects, the combination could turn out to be spectacular. To be valuable, a cancer drug didn't have to be especially effective on its own; it just had to be novel in the way it acted. And from the beginning, this was what caused so much excitement about elesclomol.

 

Safi Bahcall's partner in the founding of Synta was a cell biologist at Harvard Medical School named Lan Bo Chen. Chen, who is in his mid-sixties, was born in Taiwan. He is a mischievous man with short-cropped straight black hair and various quirks—including a willingness to say whatever is on his mind, a skepticism about all things Japanese (the Japanese occupied Taiwan during the war, after all), and a keen interest in the marital prospects of his unattached coworkers. Bahcall, who is Jewish, describes him affectionately as "the best and worst parts of a Jewish father and the best and worst parts of a Jewish mother rolled into one." (Sample e-mail from Chen: "Safi is in Israel. Hope he finds wife.")

Drug hunters like Chen fall into one of two broad schools. The first school, that of "rational design," believes in starting with the disease and working backward—designing a customized solution based on the characteristics of the problem. Herceptin, one of the most important of the new generation of breast-cancer drugs, is a good example. It was based on genetic detective work showing that about a quarter of all breast cancers were caused by the overproduction of a protein called HER2. HER2 kept causing cells to divide and divide, and scientists set about designing a drug to turn HER2 off. The result is a drug that improved survival in 25 percent of patients with advanced breast cancer. (When Herceptin's Kaplan-Meier was shown at ASCO, there was stunned silence.) But working backward to a solution requires a precise understanding of the problem, and cancer remains so mysterious and complex that in most cases scientists don't have that precise understanding. Or they think they do, and then, after they turn off one mechanism, they discover that the tumor has other deadly tricks in reserve.

The other approach is to start with a drug candidate and then hunt for diseases that it might attack. This strategy, known as "mass screening," doesn't involve a theory. Instead, it involves a random search for matches between treatments and diseases. This was the school to which Chen belonged. In fact, he felt that the main problem with mass screening was that it wasn't mass enough. There were countless companies outside the drug business—from industrial research labs to photography giants like Kodak and Fujifilm—that had millions of chemicals sitting in their vaults. Yet most of these chemicals had never been tested to see if they had potential as drugs. Chen couldn't understand why. If the goal of drug discovery was novelty, shouldn't the hunt for new drugs go as far and wide as possible?

"In the early eighties, I looked into how Merck and Pfizer went about drug discovery," Chen recalls. "How many compounds are they using? Are they doing the best they can? And I come up with an incredible number. It turns out that mankind had, at this point, made tens of millions of compounds. But Pfizer was screening only six hundred thousand compounds, and Merck even fewer, about five hundred thousand. How could they screen for drugs and use only five hundred thousand, when mankind has already made so many more?"

An early financial backer of Chen's was Michael Milken, the junk-bond king of the 1980s, who, after being treated for prostate cancer, became a major cancer philanthropist. "I told Milken my story," Chen said, "and very quickly he said, 'I'm going to give you four million dollars. Do whatever you want.' Right away Milken thought of Russia. Someone had told him that the Russians had had, for a long time, thousands of chemists in one city making compounds, and none of those compounds had been disclosed." Chen's first purchase was a batch of 22,000 chemicals, gathered from all over Russia and Ukraine. They cost about ten dollars each and came in tiny glass vials. With his money from Milken, Chen then bought a $600,000 state-of-the-art drug-screening machine. It was a big, automated Rube Goldberg contraption that could test ninety-six compounds at a time and do a hundred batches a day. A robotic arm would deposit a few drops of each chemical onto a plate, followed by a clump of cancer cells and a touch of blue dye. The mixture was left to sit for a week and then reexamined. If the cells were still alive, they would show as blue. If the chemical killed the cancer cells, the fluid would be clear.

Chen's laboratory began by testing his compounds against prostate-cancer cells, since that was the disease Milken had. Later he screened dozens of other cancer cells as well. In the first round, his batch of chemicals killed everything in sight. But plenty of compounds, including pesticides and other sorts of industrial poisons, will kill cancer cells. The trouble is that they'll kill healthy cells as well. Chen was looking for something that was selective—that was more likely to kill malignant cells than normal cells. He was also interested in sensitivity—in a chemical's ability to kill at low concentrations. Chen reduced the amount of each chemical on the plate a thousandfold and tried again. Now just one chemical worked. He tried the same chemical on healthy cells. It left them alone. Chen lowered the dose another thousandfold. It still worked. The compound came from the National Taras Shevchenko University of Kiev. It was an odd little chemical, the laboratory equivalent of a jazz musician's riff. "It was pure chemist's joy," Chen said. "Homemade, random, and clearly made for no particular purpose. It was the only one that worked on everything we tried."

Mass screening wasn't as elegant or as efficient as rational drug design. But it provided a chance of stumbling across something by accident—something so novel and unexpected that no scientist would have dreamed it up. It provided for serendipity, and the history of drug discovery is full of stories of serendipity. Alexander Fleming was looking for something to fight bacteria but didn't think the answer would be provided by the mold that grew on a petri dish he accidentally left out on his bench. That's where penicillin came from. Pfizer was looking for a new heart treatment and realized that a drug candidate's unexpected side effect was more useful than its main effect. That's where Viagra came from. "The end of surprise would be the end of science," the historian Robert Friedel wrote in the 2001 essay "Serendipity Is No Accident." "To this extent, the scientist must constantly seek and hope for surprises." When Chen gathered chemical compounds from the farthest corners of the earth and tested them against one cancer-cell line after another, he was engineering surprise.

What he found was exactly what he'd hoped for when he started his hunt: something he could never have imagined on his own. When cancer cells came into contact with the chemical, they seemed to go into crisis mode: they acted as if they had been attacked with a blowtorch. The Ukrainian chemical, elesclomol, worked by gathering up copper from the bloodstream and bringing it into cells' mitochondria, sparking an electrochemical reaction. His focus was on the toxic, oxygen-based compounds in the cell called ROS, reactive oxygen species. Normal cells keep ROS in check. Many kinds of cancer cells, though, generate so much ROS that the cell's ability to keep functioning is stretched to the breaking point, and elesclomol cranked ROS up even further, to the point that the cancer cells went up in flames. Researchers had long known that heating up a cancer cell was a good way of killing it, and there had been plenty of interest over the years in achieving that effect with ROS. But the idea of using copper to set off an electrochemical reaction was so weird—and so unlike the way cancer drugs normally worked—that it's not an approach anyone would have tried by design. That was the serendipity. It took a bit of "chemist's joy," constructed for no particular reason by some bench scientists in Kiev, to show the way. Elesclomol was wondrously novel. "I fell in love," Chen said. "I can't explain it. I just did."

 

When Freireich went to Zubrod with his idea for VAMP, Zubrod could easily have said no. Drug protocols are typically tested in advance for safety in animal models. This one wasn't. Freireich freely admits that the whole idea of putting together poisonous drugs in such dosages was "insane," and, of course, the first patient in the trial had nearly been killed by the toxic regimen. If she had died from it, the whole trial could have been derailed.

The ALL success story provided a hopeful road map for a generation of cancer fighters. But it also came with a warning: those who pursued the unexpected had to live with unexpected consequences. This was not the elegance of rational drug design, where scientists perfect their strategy in the laboratory before moving into the clinic. Working from the treatment to the disease was an exercise in uncertainty and trial and error.

If you're trying to put together a combination of three or four drugs out of an available pool of dozens, how do you choose which to start with? The number of permutations is vast. And, once you've settled on a combination, how do you administer it? A child gets sick. You treat her. She goes into remission, and then she relapses. VAMP established that the best way to induce remission was to treat the child aggressively when she first showed up with leukemia. But do you treat during the remission as well, or only when the child relapses? And, if you treat during remission, do you treat as aggressively as you did during remission induction, or at a lower level? Do you use the same drugs in induction as you do in remission and as you do in relapse? How do you give the drugs, sequentially or in combination? At what dose? And how frequently—every day, or do you want to give the child's body a few days to recover between bouts of chemo?

Oncologists compared daily 6-MP plus daily methotrexate with daily 6-MP plus methotrexate every four days. They compared methotrexate followed by 6-MP, 6-MP followed by methotrexate, and both together. They compared prednisone followed by full doses of 6-MP, methotrexate, and a new drug, cyclophosphamide (CTX), with prednisone followed by half doses of 6-MP, methotrexate, and CTX. It was endless: vincristine plus prednisone and then methotrexate every four days or vincristine plus prednisone and then methotrexate daily? They tried new drugs and different combinations. They tweaked and refined and gradually pushed the cure rate from 40 percent to 85 percent. At St. Jude Children's Research Hospital in Memphis—which became a major center of ALL research—no fewer than sixteen clinical trials, enrolling 3,011 children, have been conducted in the past forty-eight years.

And this was just childhood leukemia. Beginning in the 1970s, Lawrence Einhorn, at Indiana University, pushed cure rates for testicular cancer above 80 percent with a regimen called BEP: three to four rounds of bleomycin, etoposide, and cisplatin. In the 1970s Vincent T. DeVita, at the NCI, came up with MOPP for advanced Hodgkin's disease: mustargen, oncovin, procarbazine, and prednisone. DeVita went on to develop a combination therapy for breast cancer called CMF—cyclophosphamide, methotrexate, and 5-fluorouracil. Each combination was a variation on the combination that came before it, tailored to its target through a series of iterations. The often-asked question "When will we find a cure for cancer?" implies that there is some kind of master code behind the disease waiting to be cracked. But perhaps there isn't a master code. Perhaps there is only what can be uncovered, one step at a time, through trial and error.

When elesclomol emerged from the laboratory, then, all that was known about it was that it did something novel to cancer cells in the laboratory. Nobody had any idea what its best target was. So Synta gave elesclomol to an oncologist at Beth Israel in Boston, who began randomly testing it out on his patients in combination with paclitaxel, a standard chemotherapy drug. The addition of elesclomol seemed to shrink the tumor of someone with melanoma. A patient whose advanced ovarian cancer had failed multiple rounds of previous treatment had some response. There was dramatic activity against Kaposi's sarcoma. They could have gone on with Phase 1s indefinitely, of course. Chen wanted to combine elesclomol with radiation therapy, and another group at Synta would later lobby hard to study elesclomol's effects on acute myeloid leukemia (AML), the commonest form of adult leukemia. But they had to draw the line somewhere. Phase 2 would be lung cancer, soft-tissue sarcomas, and melanoma.

Now Synta had its targets. But with this round of testing came an even more difficult question. What's the best way to conduct a test of a drug you barely understand? To complicate matters further, melanoma, the disease that seemed to be the best of the three options, is among the most complicated of all cancers. Sometimes it confines itself to the surface of the skin. Sometimes it invades every organ in the body. Some kinds of melanoma have a mutation involving a gene called BRAF; others don't. Some late-stage melanoma tumors pump out high levels of an enzyme called LDH. Sometimes they pump out only low levels of LDH, and patients with low-LDH tumors lived so much longer that it was as if they had a different disease. Two patients could appear to have identical diagnoses, and then one would be dead in six months and the other would be fine. Tumors sometimes mysteriously disappeared. How did you conduct a drug trial with a disease like this?