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The legacy of great science

The work of Nobel Laureate Gertrude Elion lives on.

Sixty-one years after Gertrude “Trudy” Elion came to work for a predecessor company of GlaxoSmithKline, 55 years after she synthesized the first of her drugs to gain regulatory approval as a cancer therapy, 22 years after she retired, 17 years after she won the Nobel Prize for Physiology or Medicine, and eight years after she died, her legacy has wound its way to yet another medicine, this one called Arranon.

Arranon (nelarabine) Injection, a cancer drug licensed in the United States in 2005, is the product of many hands and minds. (1) Only through a sustained collaboration of industry, academia, and government were the clinical data produced to demonstrate that the drug has a role in treating certain rare forms of leukemia and lymphoma when patients have exhausted standard treatment options. (2) (See full US prescribing information for Arranon)

Yet look back far enough into this history, and there, yet again, you see the Elion legacy. In the early 1980s, Elion knew that among the compounds her laboratory had synthesized over the years there might be something that would work against leukemia or lymphoma originating in white blood cells known as T-cells. “She gave me two little glass vials, I still remember, with black tops,” says Joanne Kurtzberg, a specialist in pediatric oncology at Duke University Medical Center. In one of the vials was a precursor of Arranon.

In time, Kurtzberg would initiate clinical studies of Arranon. “It was Trudy working with Joanne who started the ball rolling” toward developing the drug for pediatric patients, says Thomas Krenitsky, long a colleague of Elion’s and now the head of his own research company. “It’s part of the legacy, it’s part of the continuum.” At the same time, Beverly Mitchell, an oncologist then at the University of North Carolina, led the early clinical work in adults. Now at Stanford University, she recalls Elion as “one of my role models.”

Elion was a member of one of the greatest drug-discovery partnerships in history. The other member was George Hitchings, a biochemist 12 years her senior, who hired her as an assistant, gave leeway to her talent, and pulled her along in his own ascent. For example, when in the 1950s Hitchings, who would share the Nobel Prize with Elion years later, successfully sponsored her before the American Society of Biological Chemists, he tried to pre-empt the challenges her election might face. (3) His words to the society, as Elion herself later related them, were these: "I know she has three strikes against her. She doesn't have a Ph.D., she is a woman, and she works for industry. Nevertheless, I am going to tell you about her."

There was already much to tell about Elion, and much more to come: Personal losses that impelled her toward medical research, a chance meeting with Hitchings, encounters with bias against women in science—and the brilliant, prodigious work that spanned half a century. It never ceased; it established new methods of drug discovery; it rushed to exploit serendipity, ranging across disciplines and diseases; and it succeeded until, in a difficult domain where success is a rarity, it came to astonish.

“You look at the list of their drugs,” says Kurtzberg, “and it is phenomenal.”

From the laboratories of Elion, Hitchings, and their co-workers came early therapies for childhood leukemia (Purinethal [mercaptopurine], often called 6-MP for 6-mercaptopurine, and Tabloid [thioguanine]); an immunosuppressant that enabled wider use of organ transplantation (Imuran [azathioprine]); the first selective anti-viral for herpes infection (Zovirax [acyclovir]); a treatment for gout (Zyloprim [allopurinol]); an anti-malarial (Daraprim [pyrimethamine]); and an antibiotic (trimethoprim, a component of Septra and Bactrim). Even after retirement, Elion contributed to the development of another therapy: the first AIDS drug, Retrovir (zidovudine), widely known as AZT for azidothymidine.

A cancer death

The need for medical research struck Elion at an early age. In 1933, when she was 15 years old, her grandfather developed stomach cancer. She spent time with him during his last days, this man who had followed her immigrant parents to America, had read to her and taken her on walks during her childhood. “I watched him die, essentially, in the hospital,” she recalled long afterward, “and that made a terrific impression on me.” At the time, she was about to enter college, and she was reflecting on what to study and what to do with her life. The experience with her grandfather decided her: “I was going to do something about cancer.”

Having moved precociously through the public schools of New York City, Elion entered Hunter College. It was a free school without which she may never have furthered her education, for the Great Depression had bankrupted the family. By age 19, she held a degree in chemistry, summa cum laude. Yet upon graduation she encountered the harsh reality that, no matter a woman’s high intellect, research positions were largely reserved for men. She secured a lab job only by working at first without pay, later to earn the grand sum of $20 a week.

With her savings, Elion went on to New York University. In 1941, she completed a master’s degree in chemistry there—and she lost the love of her life. Her fiancé died of a heart infection just before the dawn of the penicillin age. Her urgency about medical research—what she called “a matter of life and death”—was cruelly reinforced. She never married.

Looking for work again, Elion entered a new market. The United States had entered World War II, and male scientists were exchanging lab coats for military uniforms. Women in science could find their chance. Her first opportunity came in industry, but not in pharmaceuticals. She did quality control for a grocery chain, checking the acidity of pickles, the color of mayonnaise, and taking from the experience all she could learn about instrumentation. Then came a post at Johnson & Johnson, but she cooled to the work when it transpired that she would not be synthesizing medicines but rather checking the strength of sutures. As she looked for something closer to her interests, she found that Burroughs Wellcome, today merged into GSK, had a small research group in Tuckahoe, New York. Researchers there took turns interviewing job applicants. It was Hitchings’ turn the Saturday morning Elion showed up. He made the hire. She would observe later that he saw in her work a “certain intensity.”

It was 1944. Hitchings was concentrating his investigative energies on the metabolism of nucleic acids, the molecular carriers of genetic information. He sought to make drug discovery more rational, less hit-and-miss, though exactly how his path would lead to medicines was hardly obvious at the time. Not until 1944 had Oswald Avery at the Rockefeller Institute published a paper suggesting, and then only cautiously, that deoxyribonucleic acid, DNA, was the stuff of genes. Not until nine years later would James Watson and Francis Crick at Cambridge University propose the double-helix structure of DNA, which revealed how the information in this master molecule might be copied during cell replication.

Hitchings figured that he could inhibit replication of rapidly dividing cells—such as cancer cells and pathogenic microbes—by making false DNA building blocks, specifically, derivatives of the chemical bases in DNA. The trick would be to make chemical bases similar enough to those in nucleic acids that they could integrate themselves into natural metabolic pathways, yet different enough that, once integrated, they would jam the works. “Rubber donuts,” the researchers called these knockoff antimetabolites—they looked like the real thing but weren’t. Elion made her own specialty the bases called purines. They became not only prospective medicines but research tools, and observation of their effects helped to elucidate metabolic pathways until then only intuited.

Elion remarked, “Let the drug lead you to the answer nature is trying to hide from you.”

Cancer was the disease that had first moved Elion to become a researcher, and as it happened, cancer was the disease for which the Elion-Hitchings team first created new therapies. Working with collaborators at the Sloan-Kettering Memorial Institute, in New York, they created 6-MP and thioguanine in the early 1950s. 6-MP is still a mainstay in combination therapy for patients with acute lymphoblastic leukemia. The prospect for these patients, especially children, a prospect so bleak in the 1950s, has become one of the success stories in the anti-cancer crusade; among children under age five, the rate of five-year survival, sometimes deemed a cure, now exceeds 80 percent.

Quick studies, open minds

Elion and Hitchings soon turned to other diseases as well. The fundamental nature of the biology they were exploring allowed them to do that. So did their appetites to learn more. Elion, for her part, had little experience outside chemistry upon arriving at the company, and she abandoned night-school pursuit of a Ph.D. when a dean insisted she give up her job to attend classes fulltime. It didn’t much matter. She devoured chemistry at work, and branched into microbiology, enzymology, pharmacology, virology, immunology. Krenitsky recalls of the two, “They would let the compounds take them into new areas. They were quick studies. They were amazing to watch.” Far from being satisfied to lob compounds “over the fence” for clinical development, they would stay involved as the compounds advanced in the pipeline, from lab bench to bedside. Krenitsky: “Everybody tried to do that, but Trudy was a master at it. She’d argue with the medical people. She’d argue with the FDA.”

Sometimes Elion got lucky, smart-lucky. She gave years to fashioning a drug that would release 6-MP only after entering leukemic cells. Nothing came of the effort for cancer therapy. Yet, by the late 1950s, researchers outside the company had taken an interest in the effects of 6-MP on immune response. Might drugs like 6-MP prevent rejection of organ transplants? At the time, rejection thwarted transplants other than those between twins. Always quick to collaborate, Elion and Hitchings began working with what was then known as the Peter Bent Brigham Hospital, in Boston. They provided compounds screened by an immunological test their lab had set up. Joseph Murray, a transplant surgeon at the Brigham then working experimentally with dogs, came to know the two chemists from Tuckahoe as “frequent visitors” who “knew most of our dogs by name.”

From this effort resulted Imuran, one of the drugs Elion had synthesized while trying to improve upon 6-MP. It remained an essential drug in transplantation for 20 years. “Now, I didn’t start to make a compound that would do that,” Elion pointed out late in her career. “But if you listen and keep your mind open, this is what can happen. This was the story of our lives.” Surgeons first successfully used Imuran to perform a kidney transplant in 1962. In 1990, when Murray was giving his own Nobel Prize address, he noted that more than 200,000 kidney transplants had been performed worldwide.

As product followed product, the scientific contributions of Elion and Hitchings, together with those of their colleagues, merged almost indistinguishably into one another. She became head of the Department of Experimental Therapy when he moved to a higher executive rank, and she continued to make vital contributions after he retired. Her own retirement came in 1983, if retirement it can be called. A world traveller and opera buff, she took more time for interests outside her work, yet the work went on.

In 1983 the company was marshalling resources for an effort that led to the approval of AZT as the first AIDS therapy. By some accounts, Elion, with no direct hand in the accomplishment, had little to do with it. She disclaimed a part for herself. Marty St. Clair begs to differ. A virologist at GSK and an inventor of the use of AZT in treating AIDS, she says, “Trudy had everything to do with AZT. Yes, officially she was retired, but she was there working with us and counseling us. She knew exactly what we were doing.” (4)

Arranon

It was about this time that Elion was helping to spark the long train of research that would lead to Arranon. Her propensity to mentor young researchers had led to a position at Duke. There she got to know Kurtzberg, who had developed a way to test leukemia drugs in mice. Elion handed over the two compounds. With one of them, called arabinoside-guanine, or ara-G, Kurtzberg saw encouraging results.

It lacked characteristics it needed to be a medicine, however, such as solubility in water and capacity to reach target tissues in quantity. A group led by Krenitsky worked through the chemistry to overcome those issues and found more efficient routes of synthesis. It is his invention, known among his group as 506U78, that today is known as Arranon. It is a prodrug of ara-G, meaning that it is broken down to ara-G in the body. Accumulation of the drug in T-cells inhibits DNA synthesis, stopping rampant cell replication.

A minority of patients afflicted with acute lymphoblastic leukemia and lymphoblastic lymphoma, perhaps 1,600 new cases a year in the US, have the T-cell types of these cancers. (5) Thanks to medical advances including Elion’s early work, these patients have clearly brighter prospects at the time their disease is diagnosed. If, however, they do not respond to therapy, or if, after initially encouraging results, they find their disease worsening, their prospects suddenly darken. For some patients, there is then no standard therapy.

In this grim context, Arranon is no miracle cure. Like many other cancer drugs, this one is toxic, so physicians using it must watch carefully for side effects, especially including toxicity to nerves and blood-forming cells, which may be severe. (6) Having received an accelerated approval, the drug now needs further evaluation of its clinical benefit. (7)

Arranon provides, nevertheless, another treatment option, offering in some cases the prospect of sufficiently long remissions to allow bone-marrow transplants to go forward. (7) A transplant, though carrying its own risk, can replace blood-forming cells—it can sustain the thread of hope. Arranon followed by transplant was the course for a boy whose father appeared before an advisory committee of the US Food and Drug Administration to say his son had received the drug at age four, had now reached the age of 10, and was playing Little League baseball.

In a sense, then, Arranon represents the final effort by Elion to help a small group of patients who desperately needed something additional to what she could offer them before. “She started with 6-MP, and you could say that with this last drug she has completed the cycle,” remarks Neil Spector, an oncologist formally on staff at GSK and now at Duke.

“Her words still ring out to me, ‘Neil’—it’s as though she’s right next to me—‘you have to keep your eye on the patients. If you do that, the company will do fine.’” (8)

With “retirement” came more honors for Elion. In 1998, the company, which in 1970 had moved from Tuckahoe to Research Triangle Park, North Carolina, dedicated a new research center, an architectural adventure with a cubist-like façade. Its name: the Elion-Hitchings Building. The Nobel Prize had come a decade earlier. At the Stockholm awards ritual, accustomed to men in white-tie attire, Elion blazed in blue chiffon. She treated celebrity lightly, though. Arriving home, she joked about hesitantly pulling out the prize medal for a customs agent who asked her to declare any jewellery.

Such a woman leaves a legacy of spirit as well as of products. She was direct in manner and wholly unpretentious. If she was vigorous in debate, she didn’t let it get personal. Her zest, her high purpose, rubbed off on others, and she gave them the pursuit of their intellectual passions. She was generous in crediting them for what they did.

You can still hear Elion stories at GSK. There is one that goes something like this: Toward the end of her life, Elion pulls into a VIP parking space by the avant-garde structure at Research Triangle Park, an uncommon exercise of privilege by someone who typically had so little time for it. She gets out of the car, and makes her way toward an entrance. She is unknown to the parking-lot guard who now interdicts her course. She has wandered off, he suggests, and points out a parking space elsewhere. Comes the delicate reply from the seeming interloper, the inventor on 45 patents and author on more than 200 papers, the drug hunter extraordinaire and Nobel Laureate, lady of poised persistence, “Would it change your mind if I told you . . . my name is on the building?” Whereupon the guard opens the door and bids her enter.

One reason Elion kept coming back was to champion Arranon. The path of the drug was difficult, what with the need to weigh its promise against its side effects, to find the right dose and regimen, to enroll enough patients with rare cancers into trials, and to weigh its medical and commercial potential against the opportunity of other drugs in the pipeline. But then she more than most knew how hard it is to make a cancer drug.

“If you want to stay in oncology and save lives,” she once wrote in a memo of unyielding advocacy, “you need patience and vision.”

Trudy Elion participated in an Arranon project-team meeting for the last time in February of 1999. It was the week before her death. She was 81.

End notes

1 GSK worked closely with the National Cancer Institute (NCI) of the National Institutes of Health, the Children’s Oncology Group (COG) and the Cancer and Leukemia Group B, in conjunction with the Southwest Oncology Group.

2 Specifically, Arranon is indicated for the treatment patients with T-cell acute lymphoblastic leukemia and T-cell lymphoblastic lymphoma whose disease has not responded to or has relapsed following two chemotherapy regimens. This use is based on the induction of complete responses. Randomized trials demonstrating increased survival or other clinical benefit have not been conducted. Arranon has been approved for use in the US only.

3 ”When I was baptized, my father held me up and dedicated my life to the service of mankind,” Hitchings said during the Nobel Prize festivities. “I am very proud that, in some measure, I have been able to fulfill his hopes.” Hitchings and Elion shared the Nobel Prize in 1988 with a third scientist, Sir James Black, who also worked for a GSK predecessor company. Black did seminal work leading to beta-blockers for cardiovascular disease and to H2-antagonists for peptic ulcers. On the occasion of the awards, he noted his “enduring belief that our brains work best when doing focuses our thinking.” Altogether, GSK has five Nobel Laureates in its heritage. The other two are John Vane, for research into prostaglandins (among his other achievements, he clarified the way aspirin works) and Sir Henry Dale, for discoveries about the chemical transmission of nerve impulses. Vane received the award in 1982, Dale in 1936.

4 St. Clair does research in the Center of Excellence for Drug Discovery—Infectious Diseases, GSK.

5 Acute lymphoblastic leukemia (ALL) is a cancer of the blood and bone marrow. Certain immature cells in the marrow proliferate in an uncontrolled manner rather than develop into normal white blood cells called lymphocytes. These immature cells, or lymphoblasts, do not combat microbial pathogens as healthy lymphocytes do. So the patient is at high risk of infection. Anemia and bleeding are risks as well, since the proliferation of lymphoblasts in bone marrow crowds out the progenitors of red blood cells and blood platelets. Released into the bloodstream, the leukemic cells continue to divide and may spread to the liver, spleen, lymph nodes, skin, and brain. ALL is the most common cancer in children, accounting for 30 percent of cases. It may originate in either of two types of lymphocytes, T-cells or B-cells. T-ALL occurs in approximately 15 percent to 20 percent of pediatric patients and 25 percent of adult patients. Lymphoblastic lymphoma (LBL), or T-LBL when of T-cell origin, is a variant of ALL affecting the lymphatic system more than bone marrow. Patients with ALL and LBL are treated similarly.

6 Severe neurologic events have been reported with the use of nelarabine (Arranon). These events have included altered mental states including severe somnolence, central nervous system effects including convulsions, and peripheral neuropathy ranging from numbness and aresthesias to motor weakness and paralysis. There have also been reports of events associated with demyelination, and ascending peripheral neuropathies similar in appearance to Guillain-Barré syndrome. Full recovery from these events has not always occurred with cessation of therapy. Close monitoring for neurologic events is strongly recommended, and nelarabine (Arranon) should be discontinued for neurologic events of NCI Common Toxicity Criteria grade 2 or greater. In clinical studies, hematologic toxicity was the most common Grade 3 (moderate) or 4 (severe) adverse event. Hematologic toxicity included neutropenia, thrombocytopenia, anemia, febrile neutropenia, or neutropenia with infection. Other common toxicities included laboratory abnormalities including increased transaminases, gastrointestinal toxicity, fatigue, and asthenia. See full prescribing information.

7 Arranon received accelerated approval by the FDA following two Phase II trials in patients who had exhausted standard treatment options. The approval is based on the induction of complete responses, that is, responses meeting several criteria including clearance of leukemic cells from the body. Randomized trials demonstrating increased survival or other clinical benefit have not been conducted. Post-marketing evaluation to verify and describe the clinical benefit of the product will be pursued through a randomized, multi-center, Phase III trial conducted by COG and sponsored by the NCI under an agreement with GSK. The study will assess relapses and survival over four years and minimal residual disease for patients receiving standard therapy with or without Arranon. More information about trials of Arranon is available through the NCI’s Cancer Information Service at 1-800-4-CANCER and at www.cancer.gov, a website maintained by the US government.

More than 980 patients have received Arranon under clinical-trial protocols. The two Phase II clinical trials included 39 adults and 151 children with T-ALL or T-LBL. The study in children was the largest ever conducted in this patient population. The primary efficacy results comprised the cases of 28 adults and 39 children who were refractory to two regimens intended to induce remission or who had multiple relapses following those regimens. Twenty-one percent of the adults and 23 percent of the children achieved a complete response or a complete response without full hematological recovery with Arranon used as a single agent. Remissions were generally long enough to allow for a bone-marrow transplant if other conditions were met, such as the availability of a donor. Following treatment, median survival was 21 weeks for adults and 13 weeks for children.

8 Spector is Professor of Medicine, Division of Medical Oncology, Duke University Medical Center. Previously, he worked in the Center of Excellence for Drug Discovery--Oncology, GSK.

Credits

Les Prix Nobel/Nobel Lectures
Academy of Achievement
Jewish Women’s Archive
Bella International Productions, Inc.
Chemical Heritage Foundation
GlaxoSmithKline archives
Colleagues of Gertrude Elion

Trade mark information

All trade marks are the property of their respective owners:

Purinethol is a trade mark of Biogal Pharmaceutical Works Ltd
Imuran and Zyloprim are trade marks of Promethius Laboratories Inc in the USA
Septra is a trade mark of Monarch Pharmaceuticals Inc in the USA
Bactrim is a trade mark of F. Hoffmann La-Roche AG

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