NEWS

General Motors Cancer Research Foundation Awards Honor Top Cancer Innovators

Nancy Volkers

To win a coveted General Motors Cancer Research Foundation award, one thing is clear: study one area of research, focus intently on it for a decade or more, and then go with the flow.

Ronald Levy, M.D.— one of four prize winners who delivered an award lecture last month — did just that. Levy, professor of medicine and oncology at Stanford University, Palo Alto, Calif., received the Charles F. Kettering Prize for the most outstanding recent contribution to the diagnosis or treatment of cancer.



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Dr. Ronald Levy

 
Levy's focus for more than 20 years has been monoclonal antibodies to B cells. He was the first (in 1982) to successfully treat human lymphoma with a monoclonal antibody, and went on to make important contributions to the development of rituximab (Rituxan®), approved in November 1997 by the U.S. Food and Drug Administration for the treatment of patients with resistant low-grade lymphomas. Rituximab is the first new treatment for non-Hodgkin's lymphoma in 10 years.

That first lymphoma patient experienced tumor regression for 7 years after treatment with a customized monoclonal antibody; he is still alive today, said Levy. Following his treatment, Levy led a clinical trial of 52 patients, in which 33 had complete or partial remissions.

"Some of those patients have outlasted my first patient [in terms of remission]," said Levy. "They've gone 10, 11 years with no recurrence."

New Focus

These first patients received customized monoclonal antibodies; each person's cancer cells were removed and induced to provide "personalized" antibodies. To avoid the need for customization — or tailoring a monoclonal to each individual patient — focus turned to the CD20 molecule, which is expressed on normal B cells but not other cells, and is also present in 95% of B-cell lymphomas.

Work with this molecule led to rituximab, which has been given to 14,000 people since its approval, all of whom have failed standard therapy, said Levy. Future trials will test the compound as a substitute for chemotherapy and as an adjunct to chemotherapy and to bone marrow transplant, among other indications.

"I think we are just beginning to see the potential of these agents for the treatment of cancer," said Levy. He discussed results of a monoclonal antibody vaccine trial, using customized vaccines given when patients were in remission after chemotherapy. Of 32 patients, 14 responded. A randomized clinical trial is in the works.

Arnold J. Levine, Ph.D., received the Charles S. Mott Prize for the most outstanding recent contribution to the discovery of the cause or the ultimate prevention of cancer.



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Dr. Arnold J. Levine

 
Levine's focus for more than 2 decades has been the p53 gene. He isolated, cloned, and characterized the properties of the gene, a tumor suppressor gene whose mutations are implicated in a number of cancers. Levine is president and chief executive officer of Rockefeller University, New York.

Levine identified the p53 protein in the late 1970s, then cloned the gene, and by 1989 had discovered p53's function as a tumor suppressor.

Levine also discovered MDM2, a negative regulator of the p53 protein, and deduced that MDM2 binds to p53 in a cell, shuttles it into the cytoplasm, and prompts its degradation. The drug leptomycin B is targeted to this process; in cancer cells, leptomycin stops the MDM2/p53 complex from getting to the cytoplasm, increasing the concentration of p53 in the cell and causing apoptosis, or programmed cell death.

Another gene, called p19ARF, which Levine also discovered, produces a protein that stops the shuttling of the MDM2/p53 complex as well.

Robert G. Roeder, Ph.D., and Robert Tjian, Ph.D., were joint recipients of this year's Alfred P. Sloan Award, which is presented for the most outstanding recent basic science contribution to cancer research. Roeder is professor and head of the Laboratory of Biochemistry and Molecular Biology at Rockefeller University; Tjian is professor of molecular and cellular biology at the University of California at Berkeley and a Howard Hughes investigator.



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Dr. Robert G. Roeder

 


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Dr. Robert Tjian

Photo courtesy Jane Scherr.

 
Roeder and Tjian have focused on the mechanisms and regulation of gene transcription in eukaryotic cells. Both of their lectures discussed transcriptional regulation of RNA polymerases.

As for choosing one thing and focusing on it hard, this type of basic research may not be the arena in which to do that. "The challenge we face is understanding the differential regulation of 100,000 genes," said Roeder.

No small task, but both researchers have already made inroads. Tjian has determined the mechanisms that control cell- and tissue-specific gene expression. "There are tissue-specific components of transcription machinery," he said. "My lab has identified B-cell-specific and neuronal-specific machineries."

Much of Roeder's and Tjian's research has allowed for new therapeutic approaches to the control of gene expression and a better understanding of a process critical to both cancer progression and prevention.

"Ultimately, we'll have to understand how you turn genes up or down in order to understand complex diseases," said Tjian. "We should be able to understand the Achilles' heels and then take advantage of that knowledge."

GM Cancer Research Foundation Award winners are selected by "intense evaluation and competition," according to Martin Abeloff, M.D., chair of this year's Kettering Prize selection committee. Each award consists of a gold medal and $250,000.

Nominations are sent to prospective researchers by the Foundation, which has been bestowing the prizes for the past 21 years.

According to Samuel Wells, Jr., M.D., president of the Foundation, an assembly that includes members from more than 10 countries reviews the award nominations; this year, there were 140.



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Dr. Samuel Wells, Jr.

 



             
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