The Emperor of All Maladies: A Biography of Cancer (81 page)

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.

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.