格列卫   Gleevec

青蒿素   Artemisinin (Coartem)

Lasker~DeBakey Clinical Medical Research Award

Brian Druker, Nicholas Lydon, and Charles Sawyers

For the development of molecularly-targeted treatments for chronic myeloid leukemia, converting a fatal cancer into a manageable chronic condition.

Lasker~DeBakey Clinical Medical Research Award

Tu Youyou

For the discovery of artemisinin, a drug therapy for malaria that has saved millions of lives across the globe, especially in the developing world.

Award Description

Award Description

1. In 1960, Peter Nowell and the late David Hungerford, working in Philadelphia, noticed an abnormally small chromosome in cells from patients with CML.

2. Several world-class molecular biology groups then figured out that the Philadelphia chromosome generates an enzyme that promotes aberrant cell division. Although the idea held enormous appeal, many scientists thought it would not work.

3. As these results emerged in the mid 1980s, Druker, who was training to be an oncologist at the Dana-Farber Cancer Institute, and Lydon, a biochemist at Ciba-Geigy (now Novartis) realized that blocking BCR-ABL might obliterate a CML cell's ability to stir trouble.

4. By the early 1980s, the field of oncogenes had implicated unruly kinases in cancer, and Ciba-Geigy had begun to explore these proteins as potential drug targets. Lydon set up the company's tyrosine kinase inhibitor program in 1986, under the direction of Alex Matter. Their team, which included cell biologist Elizabeth Buchdunger and chemist Jürg Zimmermann, was screening large chemical collections for compounds that hamper tyrosine kinases in test tubes and inside cells.

5. They then chemically tweaked promising compounds, hoping to improve potency and selectivity. Along the way, Lydon began using a molecular tool that Druker made while studying kinases in the laboratory of Thomas Roberts (Dana-Farber Cancer Institute).

6. In 1993, Druker set up his own laboratory with a single goal in mind: Find a company that had a BCR-ABL kinase inhibitor and develop it for clinical use in CML patients. He contacted Lydon, who sent several compounds for Druker to test.

7. In 1996, Druker and Lydon reported that one of these substances, imatinib (now widely known as Gleevec), killed cultured cells that required BCR-ABL activity to survive, but did not affect a cell line that depended on a different tyrosine kinase, v-SRC.

8. Ciba-Geigy and Druker assembled a team to design the clinical trials. A key member was Charles Sawyers, who was studying BCR-ABL at the University of California, Los Angeles. To perform the first clinical trials, they enlisted the collaboration of Moshe Talpaz, an oncologist at MD Anderson Cancer Center.

9. But before they could conduct the study, the enterprise hit some bumps. Ciba-Geigy merged with Sandoz to form Novartis, and Lydon left the company soon afterward. Toxicity concerns arose, although Druker thought they could easily be handled in the clinic. Passionate in his belief that Gleevec showed tremendous promise and eager to offer patients a potentially life-saving therapy, he lobbied Novartis to move the project forward.

10. Druker, Sawyers, and Talpaz finally got the go ahead to begin a clinical trial, which started in June 1998. The first study aimed primarily to assess Gleevec's safety in chronic-phase CML patients who had not responded to interferon-based therapy or could not tolerate its side effects. These results were astonishing for a cancer drug. Typically, researchers hoped that about 10-20 percent of patients would respond in a clinical trial; in this study, 98 percent of the patients showed dramatic improvements.

11. In May of 2001, less than three years after the beginning of the first clinical study, the US Food and Drug Administration (FDA) approved the drug.

12. During the 2006 study, the scientists realized that Gleevec, as remarkable as it was, did not "cure" patients in the strictest sense.

13. But another challenge was simmering. Some patients were developing resistance to the drug and Sawyers wanted to figure out why. Initial analysis of the BCR-ABL gene revealed a sequence alteration that caused one amino acid to replace another at a particular spot in the protein. John Kuriyan (University of California, Berkeley) had recently deduced the structure of the BCR-ABL enzyme bound to Gleevec using X-ray crystallography, and the picture he produced explained what Sawyers observed.

14. Sawyers proposed to find agents that block the resistant enzyme's activity by fastening to BCR-ABL's active form, yet barring it from performing its reaction. Sprycel progressed rapidly through clinical trials and is FDA approved for patients with resistance to Gleevec. Scientists are exploring the possibility of treating people with combinations of Gleevec and second-generation medications such as Sprycel, with the hope of delaying or preventing the emergence of drug resistance.

15. Approximately 120,000 CML patients and 28,000 GIST patients are currently being treated with Gleevec worldwide.

16. Druker, Lydon, and Sawyers seized upon the known molecular defect that underlies CML, formulated the idea of tackling this root cause of the disease, crafted a specific kinase inhibitor, and designed a second-generation inhibitor when drug resistance developed. Druker, Lydon, and Sawyers have provided a stunningly successful treatment for CML and a new paradigm for cancer therapy.

1. The first known medical description of Qinghao lies in a 2000-year-old document called "52 Prescriptions" (168 BCE) that had been unearthed from a Mawangdui Han Dynasty tomb.

2. The covert operation, named Project 523 for the day it was announced—May 23, 1967—set out to battle chloroquine-resistant malaria.

3. In early 1969, Tu was appointed head of the Project 523 research group at her institute, where practitioners of traditional medicine worked side by side with modern chemists, pharmacologists, and other scientists.

4. By 1971, her team had made 380 extracts from 200 herbs.

5. At a March 1972 meeting of the Project 523 group's key participants, she reported that the neutral plant extract —number 191—obliterated Plasmodia in the blood of mice and monkeys. Later that year, Tu and her team tested the substance on 21 people with malaria in the Hainan Province, an island off the southern coast of China.

6. On November 8, 1972, she and her colleagues obtained the pure substance. They named it Qinghaosu. Tu and her colleagues subsequently determined that it had an unusual structure.

7. Subsequent clinical trials on 529 malaria cases confirmed that the crystal they had isolated delivers the antimalarial blow. Many scientists from other institutes then joined efforts to improve the extraction procedures and conduct clinical trials.

8. In October 1981, the scientific working group on the chemotherapy of malaria, sponsored by the WHO, the World Bank, and United Nations Development Business, invited Tu to present her findings at its fourth meeting.

9. In 1973, as part of her structural studies, Tu had modified artemisinin to generate a compound called dihydroartemisinin.

10. Starting in the mid 1970s, Guoqiao Li (Guangzhou College of Traditional Chinese Medicine) performed clinical trials with artemisinin and these substances.

11. In 1980, Keith Arnold (Roche Far East Research Foundation, Hong Kong) joined Li's enterprise and two years later, they published the first high-profile clinical trial of artemisinin in a peer-reviewed, western journal.

12. In 2001, the WHO signed an agreement with Novartis, the manufacturer of one of these drug combinations, Coartem®; it consists of artemether and lumefantrine, another antimalarial agent, which was originally synthesized by the Academy of Military Medical Sciences in Beijing. The company is supplying the drug at no profit to public health systems of countries where the disease is endemic. To date, Novartis has provided more than 400 million Coartem® treatments.

by Evelyn Strauss, Ph.D.

by Evelyn Strauss, Ph.D.

http://www.laskerfoundation.org/awards/2009_c_description.htm

http://www.laskerfoundation.org/awards/2011_c_description.htm