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The Philadelphia Chromosome
A Mutant Gene and the Quest to Cure Cancer at the Genetic Level
by Jessica Wapner
The Experiment
The most common treatment for cancer can be as devastating as the disease itself. Chemotherapy is carpet bombing, killing as many healthy cells as cancerous ones.
Isn’t there be a better way?
In “The Philadelphia Chromosome,” science writer Jessica Wapner chronicles the decades-long quest to develop a targeted, or “rational,” treatment that would attack cancer on the genetic level.
Her focus is imatinib, commercially available as Gleevec, one of the first successful rational drugs.
Approved by the FDA in 2001, Gleevec takes aim at a genetic mutation in which a small piece of chromosome 9 and chromosome 22 trade places, causing a rare blood cancer called chronic myeloid leukemia.
Wapner pulls no punches in describing the effects of CML on the body: “His blood, once free flowing, would turn into viscous sludge. . . . The miniscule capillaries leading to his eyes and brain would clog. His spleen would likely become profoundly enlarged. As his body began shutting down, he would bleed in his brain, in his intestines, and out of every orifice.”
As horrible a disease as CML is, it affects only about 6,000 Americans per year. Put in perspective, more than 230,000 new breast-cancer cases are diagnosed every year.
Yet Gleevec represents a promising change in approach. Until the 1990s, most pharmaceutical companies were not interested in developing drugs that work the way Gleevec works, by blocking kinases, the enzymes that jump-start different activities in cells.
Given the large number of kinases in the human body, the general consensus had been that it would be impossible to develop a compound to target the right ones.
“The development of Gleevec might never have occurred because those keeping the books . . . said that the cost of drug development would never be compensated by sales. Fortunately they did not prevail,” Dr. Robert A. Weinberg, an internationally recognized authority on the genetic basis of human cancer, wrote in the forward to Wapner’s book.
“The success of this drug proved that you could create drugs to treat rare diseases,” Wapner told The Post. “Marketing concerns had led to a lot of delays and hesitations that it turns out were needless. This drug became a blockbuster, selling $30 billion since 2001.”
In fact, Gleevec’s financial success is now under scrutiny, as more than 120 physicians recently wrote an op-ed in the journal Blood, decrying the high cost of the drug for patients who would literally die without it. And Novartis, the company that manufactures Gleevec, lost a court case last month against a manufacturer in India that sells a generic version.
While “Philadelphia Chromosome” recounts the pastiche of research that started with the discovery in a Philadelphia lab in 1959 of an unusually small chromosome in CML patients, the book’s real hero is oncologist and researcher Dr. Brian Druker, whose pivotal clinical trials lead to FDA approval of Gleevec.
Allowing his marriage and academic prestige to fall to the wayside in the 1990s, Druker tirelessly pursued a better treatment for cancer.
“A lot of people were fighting for this drug. He wasn’t the only one. But without him, this drug would not have been made,” Wapner said. “He came up against a lot of challenges. One of the stories at the heart of this book is how those challenges were overcome.”
Shortly after accepting an academic post at the Oregon Health and Sciences University in Portland, Druker began working with researchers at Ciba-Geigy, a pharmaceutical company that later became Novartis, to test the ability of a certain kinase inhibitor to kill cancerous cells. The early results were promising, but it took five frustrating years to convince the company to proceed with clinical trials in humans.
The approach researchers took in developing a drug to target the Philadelphia chromosome represents a paradigm shift in thinking about killing cancer.
Since its development, other targeted drugs have been discovered, such as Herceptin for breast cancer and Iressa for some lung cancers.
“We have this rationally designed paradigm now,” Wapner said. “There are so many efforts going on now to sequence tumors and find the mutations that seem to be causing cancer. We’re seeing researchers trying to conduct clinical trials faster, being OK with smaller numbers of patients [for trials] and finding ways for industry, academia and federal efforts to work together to get answers faster.”
Wapner sees the Gleevec story as the beginning — not only to where modern medicine is now, but to where it is going.
“I think the near-term gains will come from sequencing tumors, but at the same time we have to be open to the fact that we don’t know where the next discovery will be coming from,” she said.
“Budget cuts to the NIH and a heavy demand on results can undercut how science works. It’s rarely ‘We start at point A and get to point B and boom, we have a drug.’ That might be one way we get things to work. But good science is never wasted, and we can never forget the importance of good science.”