At face value, some of these gains might have seemed small in absolute terms—life extended by only four months. But the women enrolled in these initial trials were patients with late-stage, metastatic cancers, often heavily pretreated with standard chemotherapies and refractory to all drugs—women carrying the worst and most aggressive variants of breast cancer. (This pattern is typical: in cancer medicine, trials often begin with the most advanced and refractory cases, where even small benefits of a drug might outweigh risks.) The true measure of Herceptin’s efficacy would lie in the treatment of treatment-naive patients—women diagnosed with early-stage breast cancer who had never received any prior treatment.
In 2003, two enormous multinational studies were launched to test Herceptin in early-stage breast cancer in treatment-naive patients. In one of the studies, Herceptin treatment increased breast cancer survival at four years by a striking 18 percent over the placebo group. The second study, although stopped earlier, showed a similar magnitude of benefit. When the trials were statistically combined, overall survival in women treated with Herceptin was increased by 33 percent—a magnitude unprecedented in the history of chemotherapy for Her-2 positive cancer. “The results,” one oncologist wrote, were “simply stunning . . . not evolutionary, but revolutionary. The rational development of molecularly targeted therapies points the direction toward continued improvement in breast cancer therapy. Other targets and other agents will follow.”
On the evening of May 17, 1998, after Slamon had announced the results of the 648 study to a stunned audience at the ASCO meeting, Genentech threw an enormous cocktail party at the Hollywood Terrace, an open-air restaurant nestled in the hills of Los Angeles. Wine flowed freely, and the conversation was light and breezy. Just a few days earlier, the FDA had reviewed the data from the three Herceptin trials, including Slamon’s study, and was on the verge of “fast-tracking” the approval of Herceptin. It was a poignant posthumous victory for Marti Nelson: the drug that would likely have saved her life would become accessible to all breast cancer patients—no longer reserved for clinical trials or compassionate use alone.
“The company,” Robert Bazell, the journalist, wrote, “invited all the investigators, as well as most of Genentech’s Her-2 team. The activists came too: Marilyn McGregor and Bob Erwin [Marti Nelson’s husband] from San Francisco and Fran Visco from the National Breast Cancer Coalition.”
The evening was balmy, clear, and spectacular. “The warm orange glow of the setting sun over the San Fernando Valley set the tone of the festivities. Everyone at the party would celebrate an enormous success. Women’s lives would be saved and a huge fortune would be made.”
Only one person was conspicuously missing from the party—Dennis Slamon. Having spent the afternoon planning the next phase of Herceptin trials with breast oncologists at ASCO, Slamon had jumped into his run-down Nissan and driven home.
A Four-Minute Mile
The nontoxic curative compound remains undiscovered but not undreamt.
—James F. Holland
Why, it is asked, does the supply of new miracle drugs lag so far behind, while biology continues to move from strength to strength . . .? There is still the conspicuous asymmetry between molecular biology and, say, the therapy of lung cancer.
—Lewis Thomas,
The Lives of a Cell, 1978
In the summer of 1990, as Herceptin entered its earliest trials, another oncogene-targeted drug began its long journey toward the clinic. More than any other medicine in the history of cancer, more even than Herceptin, the development of this drug—from cancer to oncogene to a targeted therapy and to successive human trials—would signal the arrival of a new era in cancer medicine. Yet to arrive at this new era, cancer biologists would again need to circle back to old observations—to the peculiar illness that John Bennett had called a “suppuration of blood,” that Virchow had reclassified as weisses Blut in 1847, and that later researchers had again reclassified as chronic myeloid leukemia or CML.
For more than a century, Virchow’s weisses Blut had lived on the peripheries of oncology. In 1973, CML was suddenly thrust center stage. Examining CML cells, Janet Rowley identified a unique chromosomal aberration that existed in all the leukemia cells. This abnormality, the so-called Philadelphia chromosome, was the result of a translocation in which the “head” of chromosome twenty-two and the “tail” of chromosome nine had been fused to create a novel gene. Rowley’s work suggested that CML cells possess a distinct and unique genetic abnormality—possibly the first human oncogene.
Rowley’s observation launched a prolonged hunt for the mysterious chimeric gene produced by the 9:22 fusion. The identity of the gene emerged piece by piece over a decade. In 1982, a team of Dutch researchers in Amsterdam isolated the gene on chromosome nine. They called it abl.* In 1984, working with American collaborators in Maryland, the same team isolated abl’s partner on chromosome twenty-two—a gene called Bcr. The oncogene created by the fusion of these two genes in CML cells was named Bcr-abl. In 1987, David Baltimore’s laboratory in Boston “engineered” a mouse containing the activated Bcr-abl oncogene in its blood cells. The mouse developed the fatal spleen-choking leukemia that Bennett had seen in the Scottish slate-layer and Virchow in the German cook more than a century earlier—proving that Bcr-abl drove the pathological proliferation of CML cells.
As with the study of any oncogene, the field now turned from structure to function: what did Bcr-abl do to cause leukemia? When Baltimore’s lab and Owen Witte’s lab investigated the function of the aberrant Bcr-abl oncogene, they found that, like src, it was yet another kinase—a protein that tagged other proteins with a phosphate group and thus unleashed a cascade of signals in a cell. In normal cells, the Bcr and abl genes existed separately; both were tightly regulated during cell division. In CML cells, the translocation created a new chimera—Bcr-abl, a hyperactive, overexuberant kinase that activated a pathway that forced cells to divide incessantly.
In the mid-1980s, with little knowledge about the emerging molecular genetics of CML, a team of chemists at Ciba-Geigy, a pharmaceutical company in Basel, Switzerland, was trying to develop drugs that might inhibit kinases. The human genome has about five hundred kinases (of which, about ninety belong to the subclass that contains src and Bcr-abl). Every kinase attaches phosphate tags to a unique set of proteins in the cell. Kinases thus act as molecular master-switches in cells—turning “on” some pathways and turning “off” others—thus providing the cell a coordinated set of internal signals to grow, shrink, move, stop, or die. Recognizing the pivotal role of kinases in cellular physiology, the Ciba-Geigy team hoped to discover drugs that could activate or inhibit kinases selectively in cells, thus manipulating the cell’s master-switches. The team was led by a tall, reserved, acerbic Swiss physician-biochemist, Alex Matter. In 1986, Matter was joined in his hunt for selective kinase inhibitors by Nick Lydon, a biochemist from Leeds, England.
Pharmaceutical chemists often think of molecules in terms of faces and surfaces. Their world is topological; they imagine touching molecules with the tactile hypersensitivity of the blind. If the surface of a protein is bland and featureless, then that protein is typically “undruggable”; flat, poker-faced topologies make for poor targets for drugs. But if a protein’s surface is marked with deep crevices and pockets, then that protein tends to make an attractive target for other molecules to bind—and is thereby a possible “druggable” target.
Kinases, fortuitously, possess at least one such deep druggable pocket. In 1976, a team of Japanese researchers looking for poisons in sea bacteria had accidentally discovered a molecule called staurosporine, a large molecule shaped like a lopsided Maltese cross that bound to a pocket present in most kinases. Staurosporine inhibited dozens of kinases. It was an exquisite poison, but a terrible drug—possessing virtually no ability to discriminate between any kinase, active or inactive, good or bad, in most cells.
The existence of staurosporine inspired Matter. If sea bacteria could
synthesize a drug to block kinases nonspecifically, then surely a team of chemists could make a drug to block only certain kinases in cells. In 1986, Matter and Lydon found a critical lead. Having tested millions of potential molecules, they discovered a skeletal chemical that, like staurosporine, could also lodge itself into a kinase protein’s cleft and inhibit its function. Unlike staurosporine, though, this skeletal structure was a much simpler chemical. Matter and Lydon could make dozens of variants of this chemical to determine if some might bind better to certain kinases. It was a self-conscious emulation of Paul Ehrlich, who had, in the 1890s, gradually coaxed specificity from his aniline dyes and thus created a universe of novel medicines. History repeats itself, but chemistry, Matter and Lydon knew, repeats itself more insistently.
It was a painstaking, iterative game—chemistry by trial and error. Jürg Zimmermann, a talented chemist on Matter’s team, created thousands of variants of the parent molecule and handed them off to a cell biologist, Elisabeth Buchdunger. Buchdunger tested these new molecules on cells, weeding out those that were insoluble or toxic, then bounced them back to Zimmermann for resynthesis, resetting the relay race toward more and more specific and nontoxic chemicals. “[It was] what a locksmith does when he has to make a key fit,” Zimmermann said. “You change the shape of the key and test it. Does it fit? If not, you change it again.”
By the early nineties, this fitting and refitting had created dozens of new molecules that were structurally related to Matter’s original kinase inhibitor. When Lydon tested this panel of inhibitors on various kinases found in cells, he discovered that these molecules possessed specificity: one molecule might inhibit src and spare every other kinase, while another might block abl and spare src. What Matter and Lydon now needed was a disease in which to apply this collection of chemicals—a form of cancer driven by a locked, overexuberant kinase that they could kill using a specific kinase inhibitor.
In the late 1980s, Nick Lydon traveled to the Dana-Farber Cancer Institute in Boston to investigate whether one of the kinase inhibitors synthesized in Basel might inhibit the growth of a particular form of cancer. Lydon met Brian Druker, a young faculty member at the institute fresh from his oncology fellowship and about to launch an independent laboratory in Boston. Druker was particularly interested in chronic myelogenous leukemia—the cancer driven by the Bcr-abl kinase.
Druker heard of Lydon’s collection of kinase-specific inhibitors, and he was quick to make the logical leap. “I was drawn to oncology as a medical student because I had read Farber’s original paper on aminopterin and it had had a deep influence on me,” he recalled. “Farber’s generation had tried to target cancer cells empirically, but had failed because the mechanistic understanding of cancer was so poor. Farber had had the right idea, but at the wrong time.”
Druker had the right idea at the right time. Once again, as with Slamon and Ullrich, two halves of a puzzle came together. Druker had a cohort of CML patients afflicted by a tumor driven by a specific hyperactive kinase. Lydon and Matter had synthesized an entire collection of kinase inhibitors now stocked in Ciba-Geigy’s freezer in Basel. Somewhere in that Ciba collection, Druker reasoned, was lurking his fantasy drug—a chemical kinase inhibitor with specific affinity for Bcr-abl. Druker proposed an ambitious collaboration between Ciba-Geigy and the Dana-Farber Cancer Institute to test the kinase inhibitors in patients. But the agreement fell apart; the legal teams in Basel and Boston could not find agreeable terms. Drugs could recognize and bind kinases specifically, but scientists and lawyers could not partner with each other to bring these drugs to patients. The project, having generated an interminable trail of legal memos, was quietly tabled.
But Druker was persistent. In 1993, he left Boston to start his own laboratory at the Oregon Health and Science University (OHSU) in Portland. Unyoked, at last, from the institution that had forestalled his collaboration, he immediately called Lydon to reestablish a connection. Lydon informed him that the Ciba-Geigy team had synthesized an even larger collection of inhibitors and had found a molecule that might bind Bcr-abl with high specificity and selectivity. The molecule was called CGP57148. Summoning all the nonchalance that he could muster—having learned his lessons in Boston—Druker walked over to the legal department at OHSU and, revealing little about the potential of the chemicals, watched as the lawyers absentmindedly signed on the dotted line. “Everyone just humored me,” he recalled. “No one thought even faintly that this drug might work.” In two weeks, he received a package from Basel with a small collection of kinase inhibitors to test in his lab.
The clinical world of CML was, meanwhile, reeling from disappointment to disappointment. In October 1992, just a few months before CGP57148 crossed the Atlantic from Lydon’s Basel lab into Druker’s hands in Oregon, a fleet of leukemia experts descended on the historic town of Bologna in Italy for an international conference on CML. The location was resplendent and evocative—Vesalius had once lectured and taught in these quadrangles and amphitheaters, dismantling Galen’s theory of cancer piece by piece. But the news at the meeting was uninspiring. The principal treatment for CML in 1993 was allogeneic bone marrow transplantation, the protocol pioneered in Seattle by Donnall Thomas in the sixties. Allo-transplantation, in which a foreign bone marrow was transplanted into a patient’s body, could increase the survival of CML patients, but the gains were often so modest that massive trials were needed to detect them. At Bologna, even transplanters glumly acknowledged the meager benefits: “Although freedom from leukemia could be obtained only with BMT,” one study concluded, “a beneficial effect of BMT on overall survival could be detected only in a patients’ subset, and . . . many hundreds of cases and a decade could be necessary to evaluate the effect on survival.”
Like most leukemia experts, Druker was all too familiar with this dismal literature. “Cancer is complicated, everyone kept telling me patronizingly—as if I had suggested that it was not complicated.” The growing dogma, he knew, was that CML was perhaps intrinsically a chemotherapy-resistant disease. Even if the leukemia was initiated by that single translocation of the Bcr-abl gene, by the time the disease was identified in full bloom in real patients, it had accumulated a host of additional mutations, creating a genetic tornado so chaotic that even transplantation, the chemotherapist’s bluntest weapon, was of no consequence. The inciting Bcr-abl kinase had likely long been overwhelmed by more powerful driver mutations. Using a kinase inhibitor to try to control the disease, Druker feared, would be like blowing hard on a matchstick long after it had ignited a forest fire.
In the summer of 1993, when Lydon’s drug arrived in Druker’s hands, he added it to CML cells in a petri dish, hoping, at best, for a small effect. But the cell lines responded briskly. Overnight, the drug-treated CML cells died, and the tissue-culture flasks filled up with floating husks of involuted leukemia cells. Druker was amazed. He implanted CML cells into mice to form real, living tumors and treated the mice with the drug. As with the first experiment, the tumors regressed in days. The response suggested specificity as well: normal mouse blood cells were left untouched. Druker performed a third experiment. He drew out samples of bone marrow from a few human patients with CML and applied CGP57148 to the cells in a petri dish. The leukemia cells in the marrow died immediately. The only cells remaining in the dish were normal blood cells. He had cured leukemia in the dish.
Druker described the findings in the journal Nature Medicine. It was a punchy, compact study—just five clean, well-built experiments—driving relentlessly toward a simple conclusion: “This compound may be useful in the treatment of Bcr-abl positive leukemias.” Druker was the first author and Lydon the senior author, with Buchdunger and Zimmermann as key contributors.
Druker expected Ciba-Geigy to be ecstatic about these results. This, after all, was the ultimate dream child of oncology—a drug with exquisite specificity for an oncogene in a cancer cell. But in Basel, Ciba-Geigy was in internal disarray. The company had fused with its archrival across the rive
r, the pharma giant Sandoz, into a pharmaceutical behemoth called Novartis. For Novartis, it was the exquisite specificity of CGP57148 that was precisely its fatal undoing. Developing CGP57148 into a clinical drug for human use would involve further testing—animal studies and clinical trials that would cost $100 to $200 million. CML afflicts a few thousand patients every year in America. The prospect of spending millions on a molecule to benefit thousands gave Novartis cold feet.
Druker now found himself inhabiting an inverted world in which an academic researcher had to beg a pharmaceutical company to push its own products into clinical trials. Novartis had a plethora of predictable excuses: “The drug . . . would never work, would be too toxic, would never make any money.” Between 1995 and 1997 Druker flew back and forth between Basel and Portland trying to convince Novartis to continue the clinical development of its drug. “Either get [the drug] into clinical trials or license it to me. Make a decision,” Druker insisted. If Novartis would not make the drug, Druker thought he could have another chemist take it on. “In the worst case,” he recalled, “I thought I would make it in my own basement.”
Planning ahead, he assembled a team of other physicians to run a potential clinical trial of the drug on CML patients: Charles Sawyers from UCLA, Moshe Talpaz, a hematologist from Houston, and John Goldman from the Hammersmith Hospital in London, all highly regarded authorities on CML. Druker said, “I had patients in my clinic with CML with no effective treatment options remaining. Every day, I would come home from the clinic and promise to push Novartis a little.”