A City of Strings
In the late 1970s, researchers at Standford and UCSF had invented a technology known as “recombinant DNA.” They founded a biotech company called Genentech in 1976 to leverage on this technology to develop new drugs. Genentech used Recombinant DNA technology to synthesize human proteins in bacteria cells instead of extracting proteins from animal and human organs. From 1982 to 1985, Genentech had manufactured many important drugs such as human insulin, a clotting factor to treat hemophilia, and a human growth hormone – all engineered and produced in bacterial cells.
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In 1984, a team of researchers led by a German scientist named Axel Ullrich from Genentech discovered the human homolog of the neu gene, an oncogene previously discovered by Weinberg. In the summer of 1986, Ullrich told the story of the isolation of Her-2 at a UCLA seminar. Among the audience was a UCLA oncologist named Dennis Slamon. Slamon had a collection of cancer tissues from patients at UCLA. He proposed a simple collaboration to Ullrich. If Ullrich sent him the Her-2 DNA probes, Slamon could test his collection for cancer cells with hyperactive Her-2 genes. Ullrich agreed.
Slamon tested Her-2 with his collection of cancer cells. He discovered that breast cancers could be divided into two types: Her-2 positive and Her-2 negative, depending on whether or not the cancer cells amplify Her-2 by making multiple copies. Her-2 positive tumors are more aggressive, more metastatic, and more likely to kill than Her-2 negative tumors.
The association of Her-2 with an aggressive breast cancer prompted Ullrich to look for a drug to shut off the Her-2 function. In 1988, Genentech produced a mouse antibody that could inactivated Her-2 and sent it to Slamon. Slamon tested the antibody with cancer cells in a dish, the cancer cells stopped growing and died. When he injected the antibody into mice with Her-2 positive tumors, the tumors also disappeared. He concluded that the Her-2 inhibition worked in an animal model.
Both Slamon and Ullrich expected Genentech to leap at the opportunity. But Genentech got cold feet and wanted to focus on simpler and more profitable drugs. Feeling dejected, Ullrich left Genentech, leaving Slamon alone at UCLA trying to keep the Her-2 project alive at Genentech. Eventually, Slamon and Art Levinson, a molecular biologist at Genentech, convinced a tiny entrepreneurial team to push ahead with the Her-2 project. In the summer of 1990, Genentech produced a human Her-2 antibody ready for clinical trials. They called it Herceptin.
Fifteen women enrolled in Slamon’s trial at UCLA in 1992. The drug was combined with a standard chemotherapy drug, both delivered intravenously. Only five of the original cohort continued the trial to its six-month end point. One of them is Barbara Bradfield. She had told Slamon that “she was at the end of the road and had accepted what seemed inevitable,” when Slamon tried to enroll her in the trial in the summer of 1991. She survives today.
Drugs, Bodies, and Proof
By the summer of 1993, news of the Herceptin early phase trial had spread through the community. Her-2 positive breast cancer is one of the most fatal variants of the disease, and patients will try any therapy that could produce a positive response. Cancer activist urged the release of the drug to patients who had failed other therapies. These patients, they argued, could not wait for the drug to undergo the long periods of clinical trial; they wanted a life saving medicine now. For Genentech, Herceptin had not been approved by the FDA. Genentech wanted carefully executed early phase trials.
Marti Nelson, a gynecologist in California, had breast cancer when she was 33 in 1987. In 1993, six years after her initial surgery, her cancer had relapsed. She wanted to test the tumor for Her-2 sensitivity, but her HMO insisted that the test was useless because Herceptin was in investigational trials. In the summer of 1993, she contacted the Breast Cancer Action (BCA) project for help. Working through its activist networks, BCA asked several laboratories to test Nelson’s tumor. In October 1994, the tumor was found to be Her-2 positive. She would be an ideal candidate for the drug. But the news came too late. She died nine days later.
On December 4, 1994, a group of women from the BCA staged a “funeral procession” for Nelson through the Genentech campus. Unable to silence the activists, Genentech joined them. In 1995, Genentech agreed to provide an expanded access program for Herceptin, allowing oncologist to treat patients outside clinical trials.
On May 17, 1998, Slamon reported the results of the clinical trial at the 34th meetings of the American Society of Clinical Oncology in Los Angeles. In the pivotal 648 study, 469 women had received standard chemotherapy and were randomized to receive either Herceptin or a placebo. Women treated with Herceptin had shown a clear a measurable benefit. Response rates had increased by 150 percent, shrinking more tumors, and extending lives by four to five months compared to the control arm.
In 2003, two studies were launched to test Herceptin in early stage breast cancer. When the trials were combined, overall survival in women treated with Herceptin was increased by 33 percent.
A Four-Minute Mile
In 1973, Janet Rowley identified a unique chromosomal aberration in chronic myeloid leukemia (CML) cells. The abnormality, the so-called Philadelphia chromosome, resulted from a translocation in which the “head” of chromosome 22 and the “tail” of chromosome 9 had been fused to create a new gene. A team of Dutch researchers isolated the gene on Chromosome 9 in 1982. They called it abl. And in 1984, they isolated abl’s partner on chromosome 22 – a gene called Bcr. In normal cells, Bcr and abl are separate genes living on separate chromosomes. But in CML cells, the fusion of the two genes created a new chimera called Bcr-abl which coded a hyperactive kinase that causes cells to divide without control.
In the mid-1980s, a team of chemists at Ciba-Geigy was trying to develop selective kinase inhibitors. Ciba-Geigy was a pharmaceutical company in Basel, Switzerland.Â The team was headed by a Swiss physician named Alex Matter, and an English biochemist named Nick Lydon.
In 1986, Matter and Lydon discovered a simple skeletal chemical that could bind a kinase and inhibit its function. By the early 1990s. Matter and Lydon had created dozens of new molecules with similar structures. When Lydon tested these molecules on various kinases, he discovered that they were kinase inhibitors with extraordinary specificity. What Matter and Lydon needed now was a disease in which to apply this collection of chemicals.
In the late 1980s, Nick Lydon met Brian Druker at the Dana-Farber Cancer Institute. Druker, a young faculty member at the institute, was interested in CML – the cancer driven by the Bcr-abl kinase. He proposed an ambitious collaboration effort to test the kinase inhibitors on the patients at the institute. But the project was tabled because the lawyers could not agree to terms.
In 1993, Druker reconnected with Lydon after he left Boston to start his own laboratory in Portland at the Oregon Health and Science University (OHSU). Lydon informed Druker that the Ciba-Geigy team had found a molecule called CGP57148 that might inhibit Bcr-abl with high specificity. Revealing little about the potentials of the chemicals, Druker got a collaboration agreement signed between OHSU and Ciba-Geigy.
In the summer of 1993, Druker added the drug from Lydon to CML cells in a petri dish. Overnight, the CML cells were dead. He induced CML tumors into mice and then treated the mice with the drug. The tumors regressed in days, leaving behind the normal blood cells. He drew out samples of bone marrow from a few patients with CML and applied the drug to the cells in a petri dish. The leukemia cells in the marrow died immediately, leaving behind the normal blood cells. He had cured leukemia in the dish.
Druker expected Ciba-Geigy to be excited about these results. But in Basel, Ciba-Geigy has just merged with its arch rival into a pharmaceutical behemoth called Novartis. The prospect of spending millions on a drug to benefit thousands gave Novartis cold feet.
Novartis finally relented in early 1998. They changed the name of the drug to Gleevec.
In the initial phase of the study, 53 out of 54 patients receiving the drug showed a complete response within days. The remissions extended into weeks and months as the patients continued the medicine. The initial phase of the trial was a success.
The Red Queen’s Race
In the fifth year of their Gleevec trial, Charles Sawyer and Mashe Talpaz found the vast proportion of CML patients maintained deep remissions on the drug. But occasionally, a patient’s leukemia became Gleevec-resistant and stopped responding to Gleevec. Sawyers discovered that the CML cells become Gleevec-resistant by altering the structure of the molecule.
In 2005, Sawyers’s team generated another kinase inhibitor, called dasatinib, to target Gleevec-resistant Bcr-abl. The effect of this new drug on Gleevec-resistant patients was remarkable: the leukemia cells disappeared again.
Even targeted therapy was a cat-and-mouse game. When the cancer becomes resistant to the drug, we would need a different molecular variant. And when it becomes resistant to the new drug, you would need the next generation drug. Like the Red Queen’s race, we have to keep running to remain still.
In the decade since the discovery of Gleevec, 24 novel cancer-targeted drugs have been introduced and dozens more are in development. The 24 drugs have been effective against lung, breast, and prostate cancers, lymphomas, leukemias and sarcomas. Some inactivate oncogenes, others target oncogene-activated pathways.
The Red Queen’s race applies to cancer screening and cancer prevention. Circles of relationships are powerful predictors of individual behaviors. The tobacco epidemic originated as a form of metastatic social behavior. Successful cancer-prevention strategies can lapse swiftly when social behavior changes.
The Human Genome Project was completed in 2003. It will be followed by the Cancer Genome Atlas project – a compendium of every gene mutation in the most common form of cancer. Mutations in the cancer genome, Bert Vogelstein believes, come in two forms. Some are “passenger” mutations that have no impact on the biology of the cancer cell. Others are “driver” mutations that play a crucial role in the biology of a cancer cell.
The “mountains” in the cancer genome, the most frequent mutations in a particular form of cancer, have another property. They can be organized into between eleven and fifteen key cancer pathways. The dysregulation of these core pathways poses an enormous challenge for cancer therapists.
These changes provoke three directions for cancer medicine:
- Once we have identified the crucial driver mutations in any cancer, we will need to hunt for targeted therapies against these genes.
- We need to integrate the insights of cancer biology into cancer prevention to preempt the need for a million-person association study. Cancer screening can also be fortified by the molecular understanding of cancer.
- We need to integrate our understanding of abnormal genes and pathways to explain the behavior of cancer, renewing the circle of knowledge, discovery, and therapeutic intervention.
Imagine Atossa, the Persian queen who had breast cancer in 500 BC, traveling through time, appearing and reappearing in one age after the next. How would her treatment and prognosis changed in the last four millennia, and what happens to her later in the new millennium?
In 2500 BC at Imhotep’s clinic in Egypt, Imhotep provides a diagnosis, but “there is no treatment,” he says.
In 500 BC, her Greek slave cuts her tumor out – a primitive form of a mastectomy.
In 400 BC, in Thrace, Hippocrates identifies her tumor as a karkinos.
In AD 168, Claudius Galen says its a systemic overdose of black bile – cutting the tumor out would not cure it.
Medieval surgeons cut her cancer away with knives and scalpels. Some offer goat dung, lead plates, crab paste, and holy water as treatments.
In 1778, at John Hunter’s clinic in London, her cancer is assigned a stage. If the tumor is local, he recommends surgery. For advanced cancers, he advises: “remote sympathy.”
In 1890, at Halsted’s clinic in Baltimore, her breast cancer is treated with radical mastectomy.
In the early twentieth century, radiation oncologists try to destroy the tumor using X-rays. By the 1950s, her cancer is treated with a lumpectomy followed by radiation.
In the 1970s, her surgery is followed by adjuvant combination chemotherapy to diminish the chance of a relapse.
In the 1980s, besides surgery, radiation, and adjuvant chemotherapy, she is treated with hormonal and targeted therapy.
In the mid-1990s, Atossa’s genome was sequenced and found positive for BRCA-1.Â She is offered several targeted therapies to treat the illness.
In 2050, Atossa will arrive at her oncologist’s clinic with a thumb drive containing the entire sequence of her cancer’s genome. The computer would identify the mutations and pathways that are causing the cancer. Therapies will be targeted against these mutations and pathways. She will start with one combination of targeted drugs, expect to switch to a second one when her cancer mutates, and switch again when the cancer mutates again.
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