The winners are pathologist Yuan Chang, MD, of the University of Pittsburgh Cancer Institute, who is being recognized for her work investigating the Kaposi's sarcoma-associated herpesvirus; biochemist and geneticist John F.X. Diffley, PhD, of Cancer Research UK London Research Institute, who studies DNA replication – the process by which a cell copies its genetic material before it divides; and structural biologist Nikola Pavletich, PhD, a Howard Hughes Medical Institute (HHMI) investigator at MSKCC, who has determined the structures of many proteins that play roles in the formation of cancer.
The prize, named after Paul A. Marks, MD, President Emeritus of MSKCC, recognizes significant contributions to the basic understanding and treatment of cancer by scientists no more than 45 years old at the time they are nominated. The winners were selected by a committee chaired by Jeffrey M. Friedman, MD, PhD, of The Rockefeller University and the HHMI.
"The three winners have made important contributions to our understanding of the genes, proteins, and processes that can cause a cell to become cancerous," said Dr. Friedman. "While still in the early stages of their careers, each of them is already a leader in his or her field of research. The committee has great confidence that they will continue to contribute to our understanding of the biology of cancer."
Discovery of a virus that causes cancer
Dr. Chang, 43, was a co-discoverer of the Kaposi's sarcoma-associated herpesvirus (KSHV, also known as human herpesvirus 8). KSHV, the most recently discovered virus linked to human cancers, is the cause of Kaposi's sarcoma, the most common cancer in AIDS patients. Infection with KSHV can also lead to a type of B-cell lymphoma and Castleman's disease, a noncancerous but severe disorder characterized by enlargement of the lymph nodes.
For decades, Kaposi's sarcoma was believed to be caused by an infectious agent. But until Dr. Chang and her husband and collaborator, Patrick Moore, MD, MPH, discovered KSHV in 1994, the virus that causes the disease remained unknown.
Infection with the virus is uncommon in North America and usually doesn't cause symptoms in healthy individuals. But in parts of Africa, KSHV infection is much more widespread, and Kaposi's sarcoma can be the most common cancer in the population. Individuals who are infected with KSHV and whose immune systems are suppressed, such as those with HIV/AIDS, have a high likelihood for developing one of the KSHV-associated disorders.
"Yuan Chang's discovery of KSHV was a seminal breakthrough that has enabled all subsequent understanding of how the virus causes disease, as well as the diagnosis and potential treatment of KSHV infection," said Elliott D. Kieff, MD, PhD, Harriet Ryan Albee Professor of Medicine and a professor of microbiology and molecular genetics at Harvard Medical School. "Her basic and clinical research has transformed our understanding of the most common malignancy in people infected with HIV."
Since discovering KSHV, Dr. Chang has continued to study the biology of the virus. In 1996, she and her colleagues published the DNA sequence of KSHV, revealing that the virus has pirated several cellular genes that have proven useful in understanding the properties of other tumor viruses.
"We are studying the genes in KSHV to gain insights into the processes in cells that lead to cancer," Dr. Chang said. "The virus carries genetic material that causes cancer into cells. We are finding that the same pathways affected by these viral genes are also altered in cancers not caused by viruses," she said.
Examining how DNA replicates in the cell
Dr. Diffley, 45, has been recognized for his work exploring DNA replication. Proper DNA replication is essential to maintaining the integrity of the genome, and loss of this integrity can lead to cancer. Working primarily with yeast, Dr. Diffley has studied how replication begins, the mechanisms that ensure replication is triggered only once during each cell cycle, and what happens when replication is not initiated properly.
"The extraordinary clarity of his observations, the crispness of his data, and the beautiful logic of his ideas and discoveries have been characteristic of John's research," said Bruce Stillman, PhD, Director and Chief Executive Officer of the Cold Spring Harbor Laboratory on Long Island, New York, who was Dr. Diffley's postdoctoral advisor. "He has always addressed important problems and has been at the forefront of solving them. I would venture to say that John is one of the best scientists today who focuses on how our genome is inherited from one cell generation to the next."
Dr. Diffley's work has led to the discovery of several important proteins involved in DNA replication. In the late 1980s, he isolated the first protein known to be involved in binding to chromosome origins, called ABF1. Origins are the sites where replication is initiated, and this protein plays a role in that initiation. In 1992, his laboratory helped describe a protein called ORC, which is required to initiate replication. Since then, his team has discovered and characterized several other proteins required for DNA replication to begin, including one called the pre-replicative complex. He also contributed to work showing that cyclin-dependent kinases – enzymes that act as switches to control the progression of the cell cycle – can both trigger and prevent initiation, depending on what is going on inside the cell.
Dr. Diffley also has characterized the effects of DNA-damaging agents (such as radiation and certain drugs) on replication and found that the checkpoint where DNA damage occurs plays a central role in regulating the response of replication to this damage. This response is important: When DNA is damaged, the cell must stop dividing so the error can be repaired and not be passed on to other cells.
"There is still much to learn about the basic mechanisms of replication. But at the same time, we are shifting our focus to understanding how the misregulation of replication leads to tumor formation," said Dr. Diffley. "We are also translating the work we've done in yeast to human cells, in particular how targeting DNA damage checkpoints might lead to new approaches for killing cancer cells."
Using structural biology to understand cancer Dr. Pavletich, who will be 38 in November, is the Stephen and Barbara Friedman Chair in the Sloan-Kettering Institute (SKI), the basic research arm of MSKCC. Dr. Pavletich leads a laboratory that uses x-ray crystallography to discern the three-dimensional structures of proteins involved in cancer. "Molecular structures can help explain cancer development and spread and a tumor's response to chemotherapy," he said. "An understanding of what these molecules look like, the properties of their shapes, and how these shapes might fit with other molecules is extremely valuable for developing anticancer drugs."
In 1994, Dr. Pavletich produced the first 3-D image of the p53 tumor suppressor, which normally puts the brakes on rampant cell growth. Abnormalities in p53 have been implicated in nearly half of all human cancers. In the following years, he and his team elucidated the structures of proteins that run the cell's growth program – termed the cell division cycle – showing how they control growth and how their mutation contributes to cancer. And last year, Dr. Pavletich discovered a new function for BRCA2. Mutations in the BRCA2 gene can increase the risk of breast and ovarian cancers. By showing that the structure of the BRCA2 protein is similar to other proteins that bind broken DNA strands, Dr. Pavletich and his colleagues demonstrated that BRCA2 interacts directly with DNA to help repair genetic damage. An inability to correct this damage can lead to cancer.
"In a number of prominent cases, the protein structures solved by Nikola's laboratory were either firsts in the field or at least one of the first analyses of their kind," said David M. Livingston, MD, Emil Frei Professor of Genetics and Medicine at Harvard Medical School and a leading cancer biologist. "The sheer output of such structures has been extraordinary. Yet in addition to this volume, a remarkable depth of new insight into fundamental biochemical and biological mechanisms has emerged from his razor-sharp interpretations. Reading Nikola's papers has repeatedly transformed my understanding of how key molecular events occur."
Dr. Pavletich, who was recently named Chairman of the new Structural Biology Program at SKI, hopes to apply his research and lead others in the program to see how structural biology can enhance the development of more effective anticancer drugs. "Structural biology can help streamline drug discovery by delineating the structures of target proteins bound to compounds that are marginally effective, laying down a road map for improving the compounds and making them into real drugs," he explained. "Investigators can also analyze the structures of aberrant proteins involved in cancer to pinpoint potential targets to which anticancer drugs might bind."
"Like the previous winners of the Paul Marks Prize, these young independent investigators have made definable contributions to a range of disciplines related to cancer biology," said MSKCC President Harold Varmus, MD. "From virology to structural biology to cell cycles and genetics, their distinctive and creative discoveries play an important role in our understanding of cancer and may eventually aid in the development of new treatments for this disease."
The first Paul Marks Prize was awarded in 2001. The Prize is presented every other year. This year's winners will be honored at a dinner on December 3 and will speak about their work at a public symposium at MSKCC's Rockefeller Research Laboratories building on December 4.
Dr. Chang is a Professor of Pathology in the Department of Pathology at the University of Pittsburgh Cancer Institute in Pennsylvania. She received her MD degree from the University of Utah College of Medicine in Salt Lake City.
Dr. Diffley is a Principal Scientist at Cancer Research UK London Cancer Research Institute (formerly the Imperial Cancer Research Fund). He received his PhD degree in Biology from New York University.
Dr. Pavletich received his PhD degree from the Johns Hopkins University School of Medicine. He is Chairman of the Structural Biology Program and leads the Laboratory of Structural Biology of Oncogenes and Tumor Suppressors at SKI.
In addition to Dr. Friedman, other members of the selection committee were Richard Axel, MD, of Columbia University and the HHMI; Steven J. Burakoff, MD, of the NYU Cancer Institute and the Skirball Institute of Biomolecular Medicine; William G. Kaelin, Jr., MD, of the Dana-Farber Cancer Institute and the HHMI; Titia de Lange, PhD, of The Rockefeller University; Joan Massagué, PhD, of MSKCC and the HHMI; and Stanley R. Riddell, MD, of the Fred Hutchinson Cancer Research Center. Dr. Varmus was an ex officio member of the committee.
Memorial Sloan-Kettering Cancer Center is the world's oldest and largest private institution devoted to prevention, patient care, research, and education in cancer. Our scientists and clinicians generate innovative approaches to better understand, diagnose, and treat cancer. Our specialists are leaders in biomedical research and in translating the latest research to advance the standard of cancer care worldwide.
About the Paul Marks Prize for Cancer Research
The Paul Marks Prize for Cancer Research is named for Paul A. Marks, MD, President Emeritus of Memorial Sloan-Kettering Cancer Center (MSKCC). Dr. Marks led MSKCC from 1980 to 1999 as its President and Chief Executive Officer. The Prize was created by MSKCC's Boards of Overseers and Managers at the time of Dr. Marks's retirement to honor his many contributions as a distinguished scientist and leader, as well as a teacher of young scientists. It is awarded to researchers who are no more than 45 years old at the time they are nominated.
The first Paul Marks Prize was given in December 2001. Winners of that Prize were:
Titia de Lange, PhD, of The Rockefeller University. Dr. de Lange was honored for her discoveries of the proteins that bind telomeres, the sections of DNA at the ends of chromosomes.
Stephen J. Elledge, PhD, of Baylor College of Medicine and the Howard Hughes Medical Institute (HHMI). Dr. Elledge identified two related but independent systems that have important roles in the cell cycle.
William G. Kaelin, Jr., MD, of the Dana-Farber Cancer Institute and the HHMI. Dr. Kaelin discovered the novel mechanism used by a normal protein, called VHL, to protect against tumors.
Xiaodong Wang, PhD, of the University of Texas Southwestern Medical Center and the HHMI. Dr. Wang unveiled a key, previously unsuspected biochemical step in the process of programmed cell death in mammalian cells.
The Paul Marks Prize is presented every other year with a $125,000 award to be shared and a dinner and a scientific symposium in New York City.
Winners of the 2003 Paul Marks Prize for Cancer Research
Yuan Chang is a Professor of Pathology in the Department of Pathology at the University of Pittsburgh Cancer Institute in Pennsylvania. She is being recognized for her work investigating the Kaposi's sarcoma-associated herpesvirus, the most recently discovered virus linked to human cancers. Dr. Chang discovered the virus in 1994 and since then has continued to study the biology of it. She received her MD degree from the University of Utah College of Medicine in Salt Lake City. She was a resident at the University of California, San Francisco, and did a fellowship at Stanford University.
John F.X. Diffley is a Principal Scientist at Cancer Research UK London Cancer Research Institute (formerly the Imperial Cancer Research Fund). He is being honored for his work studying DNA replication – the process by which a cell copies its genetic material before it divides. Proper DNA replication is essential to maintaining the integrity of the genome, and loss of this integrity can lead to cancer. Dr. Diffley received his PhD degree in Biology from New York University. He did a postdoctoral fellowship at Cold Spring Harbor Laboratory on Long Island, New York.
Nikola P. Pavletich is Chairman of the Structural Biology Program in the Sloan-Kettering Institute at Memorial Sloan-Kettering Cancer Center and leads the Laboratory of Structural Biology of Oncogenes and Tumor Suppressors. He is also an investigator in the Howard Hughes Medical Institute. He has used x-ray crystallography to determine the three-dimensional structures of many proteins that play roles in the formation of cancer when they are mutated. These proteins include p53, which is implicated in nearly half of all human cancers, and BRCA2, which is linked to hereditary breast and ovarian cancers. Dr. Pavletich received his PhD degree from The Johns Hopkins University School of Medicine. He did a postdoctoral fellowship at the Massachusetts Institute of Technology.