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. Jurg 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 river, 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."
In early 1998, Novartis finally relented. It would synthesize and release a few grams of CGP57148, just about enough to run a trial on about a hundred patients. Druker would have a shot--but only one shot. To Novartis, CGP57148, the product of its most ambitious drug-discovery program to date, was already a failure.
I first heard of Druker's drug in the fall of 2002. I was a medical resident triaging patients in the emergency room at Mass General when an intern called me about a middle-aged man with a history of CML who had come in with a rash. I heard the story almost instinctively, drawing quick conclusions. The patient, I surmised, had been transplanted with foreign bone marrow, and the rash was the first blush of a cataclysm to come. The immune cells in the foreign marrow were attacking his own body--graft-versus-host disease. His prognosis was grim. He would need steroids, immunosuppressives, and immediate admission to the transplant floor.
But I was wrong. Glancing at the chart in the red folder, I saw no mention of a transplant. Under the stark neon light of the examining room when he held out his hand to be examined, the rash was just a few scattered, harmless-looking papules--nothing like the dusky, mottled haze that is often the harbinger of a graft reaction. Searching for an alternative explanation, I quickly ran my eye through his list of medicines. Only one drug was listed: Gleevec, the new name for Druker's drug, CGP57148.*
The rash was a minor side effect of the drug. The major effect of the drug, though, was less visible but far more dramatic. Smeared under the microscope in the pathology lab on the second floor, his blood cells looked extraordinarily ordinary--"normal red cells, normal platelets, normal white blood cells," I whispered under my breath as I ran my eyes slowly over the three lineages. It was hard to reconcile this field of blood cells in front of my eyes with the diagnosis; not a single leukemic blast was to be seen. If this man had CML, he was in a remission so deep that the disease had virtually vanished from sight.
By the winter of 1998, Druker, Sawyers, and Talpaz had witnessed dozens of such remissions. Druker's first patient to be treated with Gleevec was a sixty-year-old retired train conductor from the Oregon coast. The patient had read about the drug in an article about Druker in a local newspaper. He had called Druker immediately and offered to be a "guinea pig." Druker gave him a small dose of the drug, then stood by his bedside for the rest of the afternoon, nervously awaiting any signs of toxicity. By the end of the day there were no adverse effects; the man was still alive. "It was the first time that the molecule had entered a human body, and it could easily have created havoc, but it didn't," Druker recalled. "The sense of relief was incredible."
Druker edged into higher and higher doses--25, 50, 85, and 140 mg. His cohort of patients grew as well. As the dose was escalated in patients, Gleevec's effect became even more evident. One patient, a Portland woman, had come to his clinic with a blood count that had risen to nearly thirtyfold the normal number; her blood vessels were engorged with leukemia, her spleen virtually heaving with leukemic cells. After a few doses of the drug, Druker found her counts dropping precipitously, then normalizing within one week. Other patients, treated by Sawyers at UCLA and Talpaz in Houston, responded similarly, with blood counts normalizing within a few weeks.
News of the drug spread quickly. The development of Gleevec paralleled the birth of the patient chat room on the Internet; by 1999, patients were exchanging information about trials online. In many cases, it was patients who informed their doctors about Druker's drug and then, finding their own doctors poorly informed and incredulous, flew to Oregon or Los Angeles to enroll themselves in the Gleevec trial.
Of the fifty-four patients who received high doses of the drug in the initial phase I study, fifty-three showed a complete response within days of starting Gleevec. Patients continued the medicine for weeks, then months, and the malignant cells did not visibly return in the bone marrow. Left untreated, chronic myeloid leukemia is only "chronic" by the standards of leukemia: as the disease accelerates, the symptoms run on a tighter, faster arc and most patients live only three to five years. Patients on Gleevec experienced a palpable deceleration of their disease. The balance between normal and malignant cells was restored. It was an unsuppuration of blood.
By June 1999, with many of the original patients still in deep remissions, Gleevec was evidently a success. This success continues; Gleevec has become the standard of care for patients with CML. Oncologists now use the phrases "pre-Gleevec era" and "post-Gleevec era" when discussing this once-fatal disease. Hagop Kantarjian, the leukemia physician at the MD Anderson Cancer Center in Texas, recently summarized the impact of the drug on CML: "Before the year 2000, when we saw patients with chronic myeloid leukemia, we told them that they had a very bad disease, that their course was fatal, their prognosis was poor with a median survival of maybe three to six years, frontline therapy was allogeneic transplant . . . and there was no second-line treatment. . . . Today when I see a patient with CML, I tell them that the disease is an indolent leukemia with an excellent prognosis, that they will usually live their functional life span provided they take an oral medicine, Gleevec, for the rest of their lives."
CML, as Novartis noted, is hardly a scourge on public health, but cancer is a disease of symbols. Seminal ideas begin in the far peripheries of cancer biology, then ricochet back into more common forms of the disease. And leukemia, of all forms of cancer, is often the seed of new paradigms. This story began with leukemia in Sidney Farber's clinic in 1948, and it must return
to leukemia. If cancer is in our blood, as Varmus reminded us, then it seems only appropriate that we keep returning, in ever-widening circles, to cancer of the blood.
The success of Druker's drug left a deep impression on the field of oncology. "When I was a youngster in Illinois in the 1950s," Bruce Chabner wrote in an editorial, "the world of sport was shocked by the feat of Roger Bannister. . . . On May 6, 1954, he broke the four-minute barrier in the mile. While improving upon the world record by only a few seconds, he changed the complexion of distance running in a single afternoon. . . . Track records fell like ripe apples in the late 50s and 60s. Will the same happen in the field of cancer treatment?"
Chabner's analogy was carefully chosen. Bannister's mile remains a touchstone in the history of athletics not because Bannister set an unbreachable record--currently, the fastest mile is a good fifteen seconds under Bannister's. For generations, four minutes was thought to represent an intrinsic physiological limit, as if muscles could inherently not be made to move any faster or lungs breathe any deeper. What Bannister proved was that such notions about intrinsic boundaries are mythical. What he broke permanently was not a limit, but the idea of limits.
So it was with Gleevec. "It proves a principle. It justifies an approach," Chabner continued. "It demonstrates that highly specific, non-toxic therapy is possible." Gleevec opened a new door for cancer therapeutics. The rational synthesis of a molecule to kill cancer cells--a drug designed to specifically inactivate an oncogene--validated Ehrlich's fantasy of "specific affinity." Targeted molecular therapy for cancer was possible; one only needed to hunt for it by studying the deep biology of cancer cells.
Siddhartha Mukherjee - The Emperor of All Maladies: A Biography of Cancer Page 52
