The prize, named after Paul A. Marks, 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, a professor at The Rockefeller University and an HHMI investigator.
"While still in relatively early stages of their careers, the three winners already are leaders in their respective fields of research," said Dr. Friedman. "Each has made significant contributions to our understanding of the genes, signaling pathways, and processes that regulate cell proliferation and lead to the formation of tumors, their spread, and their response to treatment. The selection committee is confident that these three young scientists will continue to play key roles in cancer research in the future."
Building a better mouse
Dr. Jacks has taken novel approaches to creating better, more accurate models of a variety of human cancers in mice. Much of his research has focused on the oncogene K-Ras, which is implicated in 30 percent of non-small cell lung cancers, 90 percent of pancreas cancers, and 50 percent of colon cancers, as well as many other tumors. He also has studied mutations of p53 and other tumor suppressor genes. His laboratory has engineered mice in which researchers can precisely regulate where and when mutations of K-Ras, p53, and other cancer-causing genes are activated. This allows them to study cancer in its very earliest stages.
"Tyler Jacks' leading work in the creation and study of genetically altered mice has taught us important lessons about the role of tumor suppressor genes and oncogenes in cell transformation and tumor pathogenesis," said Robert A. Weinberg, a founding member of the Whitehead Institute for Biomedical Research and a professor of biology at MIT.
"There are many applications for these mouse models," Dr. Jacks said. "We can use them to identify biomarkers [such as proteins or peptides] that indicate the presence of disease, which will lead to the development of better screening tests for cancer. In addition we can use them to develop better imaging technologies, which can give us a very detailed understanding of how cancers first arise." Developing these technologies is especially crucial for tumors such as those of the lung and pancreas, which in humans are usually diagnosed at a late stage when treatment is least effective.
These mouse models can also be used to test various therapies, both conventional and experimental, including drugs that are targeted to block a particular pathway. "So far, our models have shown that certain drugs predicted to be effective in treating particular cancers are not, and these results have foreshadowed failures later seen in the clinic," said Dr. Jacks. Another of his goals is to develop better chemopreventive agents, which would eliminate cells before they become cancerous or before they spread.
Machinery of cell growth and death
Dr. Lowe is exploring the molecular and genetic machinery of apoptosis (programmed cell death) and cellular senescence (in which cells irreversibly stop proliferating but remain alive). These normal cellular processes are disrupted in cancer cells, which accounts for how tumors are able to grow and spread. Much of his work has focused on the tumor suppressor gene p53, which is mutated in about half of all cancers. His work has shown how changes in p53 can lead to the development of tumors and how the disruption of p53 can affect a tumor's response to therapy, leading to drug resistance.
Like Dr. Jacks, Dr. Lowe's work also has centered on the development of advanced, groundbreaking mouse models. "These models have allowed us to understand the evolution of cancer ¨C how it progresses and responds to therapy," said Dr. Lowe. One particular area of his research has been using these models to make sense of apoptosis and senescence so that these processes can be restored to cancer cells, thus allowing traditional chemotherapy drugs to destroy them.
Another focus with his mouse model research is to gain insight into the genetic factors that influence the effectiveness of targeted therapies. "Our long-term goal is to use these models to determine how to make chemotherapy agents that are more effective and also to develop new combination therapies," Dr. Lowe said.
"Scott Lowe is one of the most innovative and energetic young investigators in the field of cancer research, particularly focusing on development of new therapeutic approaches," said Bruce Stillman, President of CSHL. "I believe he has made major contributions in his career and will continue to do so in the future."
In his most recent research, Dr. Lowe has used the relatively new technique of RNA interference (RNAi) to more closely regulate the expression of genes in mice.
Characterizing cellular communication
Dr. Wrana's work has focused on the Transforming Growth Factor-beta (TGF-À) family of cell signaling proteins that regulate cell growth and function. These proteins are
secreted by cells and then go back to the same cell or one nearby to control behavior.
"TGF-À is interesting from a cancer perspective because it can both block and promote cancer growth," Dr. Wrana said. His laboratory helped to define the components of the TGF-À signaling pathway and determine how its receptors are internalized by cells, a critical event that allows cells to function.
"Dr. Wrana's demonstration that a key component of the TGF-À pathway is mutated in some forms of colorectal cancer was critical in establishing the role of this pathway in restraining the growth of particular human tumors," said Anthony J. Pawson, Senior Investigator and Director of Research at the SLRI. "His work has provided seminal contributions to our current understanding of how the TGF-À pathway works, and his ongoing research is yielding innovative approaches to the analysis of cellular signaling networks."
Most recently, Dr. Wrana has begun using the technology of high-throughput screening to study not only TGF-À but other key signaling pathways as well. "These different pathways work together to create a code or language that tells cells how to behave," said Dr. Wrana. "What is really important from a cancer perspective is not just the individual pathways but how the interaction of these pathways leads to cancer. This transformation becomes very complex as the cancer progresses and more mutations and more pathways become involved," he said.
"My dream goal is to discover drugs that target the interactions of these pathways," he added. The use of robotics and high-throughput technology will allow his lab to explore these interactions and test compounds in many different human cell lines.
"The recipients of this year's Paul Marks Prize all have made fundamental discoveries that open up broad new avenues for cancer research," said MSKCC President Harold Varmus. "At the same time, despite all of their accomplishments, I believe they are only at the beginning of what they will ultimately contribute toward our greater understanding of many of the genes, proteins, and signaling pathways that contribute to the formation of cancer."
The Paul Marks Prizes have been awarded every other year since they were established in 2001. This year's winners will be honored at a luncheon on December 1 and will speak about their work at a public symposium held after the luncheon at Memorial Sloan-Kettering Cancer Center.
Tyler E. Jacks, PhD, is the David H. Koch Professor of Biology at the Massachusetts Institute of Technology and Director of the MIT Center for Cancer Research, as well as an HHMI investigator. He received his PhD degree in biochemistry from the University of California, San Francisco.
Scott W. Lowe, PhD, is a professor at Cold Spring Harbor Laboratory and Deputy Director of the Cold Spring Harbor Laboratory Cancer Center. He was appointed as an HHMI investigator earlier this year. He received his PhD degree in biology from MIT.
Jeff Wrana, PhD, is a professor of Medical Genetics and Microbiology at the University of Toronto and a Senior Scientist in the Program in Molecular Biology and Cancer in the Samuel Lunenfeld Research Institute, part of Mount Sinai Hospital. He is also an HHMI international scholar. He received his PhD degree in biochemistry from the University of Toronto.
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 New York University Cancer Institute and the Skirball Institute of Biomolecular Medicine; Stephen J. Elledge, PhD, of the Department of Biochemistry at Baylor College of Medicine and the HHMI; William G. Kaelin, Jr., MD, of the Dana-Farber Cancer Institute and the HHMI; Titia de Lange, PhD, of The Rockefeller University; Dan R. Littman, MD, PhD, of the New York University Medical Center, the Skirball Institute, and the HHMI; Joan Massagu, PhD, of MSKCC and the HHMI; and Stanley R. Riddell, MD, of the Fred Hutchinson Cancer Research Center. Dr. Varmus is 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. Its scientists and clinicians generate innovative approaches to better understand, diagnose, and treat cancer. Memorial Sloan-Kettering specialists are leaders in biomedical research and in translating the latest research to advance the standard of cancer care worldwide.