MIT Reports to the President 1997-98

CENTER FOR CANCER RESEARCH

The Center for Cancer Research was established in 1973 to study fundamental biological processes related to cancer. The goals of the Center's research can be generally stated as developing an understanding of (1) the genetic and molecular basis of cancer, (2) how alterations in cellular processes affect cell growth and behavior, and (3) how the immune system develops and recognizes antigens. These goals are related to the Center's major research programs in oncogenes and mammalian genetics, molecular, cellular and developmental biology, and immunology. Approximately 231 people work in the Center, distributed among the research laboratories of 12 faculty. In addition, three faculty members in the Whitehead Institute, two in Biology, and one in Chemistry are Affiliate Members of the CCR.

Financial support for research in the Center comes from many sources. The core of this support, which provides much of the funds for administration, partial faculty salary support, and central research facilities (i.e. glass washing facility, specialized laboratories and partial support for new faculty), is a Center Core grant from the National Cancer Institute. The current term extends to April 30, 2000. In addition to the core grant, the Center's faculty have a total of 46 fully funded projects (plus over half a million dollars of competitive support in fellowships for postgraduate studies). This support comes largely from the National Institutes of Health and the Howard Hughes Medical Institute and from a variety of foundations supporting research in particular disease areas (American Cancer Society, Hereditary Disease Foundation, Muscular Dystrophy Association, National Neurofibromatosis Foundation, etc.). This latter type of support is particularly valuable for starting projects which later mature into federally funded grants. The Center's success in attracting grant support is a reflection of the excellence of the research and educational activities of its faculty members. The FY97 research volume was approximately $11.6 million, which does not include $3.9 million in additional support from the Howard Hughes Medical Institute.

Several groups in the Center study the identities and functions of oncogenes and tumor suppressor genes. This work includes the recent identification of two genes disposing to acute myeloid leukemia as well as basic molecular studies on other oncogenes and tumor suppressor genes that regulate gene expression controlling the cell cycle and tumor growth. Another focus is on the biochemical mechanisms controlling RNA transcription and splicing, including studies of genes of the AIDS virus, HIV.

The immunologists in the Center study the development of cytotoxic and helper T lymphocytes, their antigen-specific receptors, and the molecular mechanisms of antigen presentation as well as the development and memory properties of B lymphocytes which produce antibodies. Since the immune response to tumors is poorly understood, these basic studies are crucial to a more profound analysis of tumor rejection. Immune cells can destroy cancer cells and it may be possible to stimulate this process.

The cell biologists study cell surface proteins involved in cellular adhesion and migration, as well as cytoskeletal proteins involved in cell motility and shape. Alterations in cell adhesion proteins contribute to the malignant phenotype of tumor cells including involvement in invasion, metastasis and angiogenesis. These proteins as well as cytoskeletal proteins are important targets for antitumor drugs, and deeper understanding of their structure and function should contribute to better therapeutic agents.

Since the cellular processes of development and cancer have much in common, useful insights into the behavior of tumor cells can be obtained from studies of normal embryos; several projects in the Center focus on developmental processes. Recent advances in the generation of transgenic mice and mice with mutations in targeted genes are being exploited to investigate the roles of a variety of proteins important in tumorigenesis, including oncogene proteins, tumor suppressor genes, cell adhesion receptors, T-cell receptors and protein kinases.

Major recent research advances include:

• The development by the Hopkins lab of efficient procedures for insertional mutagenesis in the model organism, zebrafish. These procedures allow identification of novel genes controlling development, cancer and other processes. A major screen for such mutations is now underway.
• The discovery and isolation by the Housman laboratory of genes causing acute myeloid leukemia. Two such genes were identified by sophisticated genomic analyses. Both represent fusions of other genes and their structures provide fascinating insights into the mechanisms for initiation of leukemia.
• The generation by the Hynes laboratory of strains of mice lacking vital cell adhesion molecules leading to failures in protection against bacterial infections; these mice provide models for human immunodeficiency diseases. Other mutant mice developed in the laboratory are models for human bleeding disorders.
• The discovery by the Lees laboratory of a novel level of regulation of gene transcription factors important in control of the cell cycle, which is altered in cancer cells.
• The discovery by the Liu lab of a target for a very promising anticancer drug inhibiting tumor angiogenesis, the development by tumors of blood vessels necessary for their survival.
• The development by the Tonegawa lab of methods for ablating specific genes at defined locations in the brain in order to study the processes of learning and memory.

In addition to its strengths in basic research, the CCR performs an important role in training future researchers in biomedical science, including undergraduate and graduate students, postdoctoral and clinical fellows. The faculty of the Center fulfill critical roles in the educational programs of the Department of Biology. Our colleague, Dr. Phillip Sharp, has served as Head of the Department for the past seven years. Extensive collaborations exist with medical schools, hospitals and the biotechnology/pharmaceutical industries. Thus, the research in the CCR has a major impact both on the fundamental understanding of cancer and on translation to and from the clinical arena.

A major strength of the Center remains its attractiveness as an environment for the training of young scientists. The Center has 49 graduate and undergraduate students and 65 postdoctoral fellows/associates. The Center also benefited from a number of international faculty-rank visitors during the past year.

It is a pleasure to report the following honors and awards to faculty of the Center during this past year:

• Jianzhu Chen was named the Latham Family Career Development Professor.
• Nancy Hopkins was elected a Fellow of the American Academy of Arts and Sciences.
• David Housman was elected to the Institute of Medicine.
• Tyler Jacks is the recipient of the 1998 American Society for Biochemistry and Molecular Biology--Amgen Award, which recognizes significant achievements in the application of biochemistry and molecular biology to the understanding of disease by an investigator within 15 years of receiving a doctorate.
• Frank Solomon was a recipient of the Frank E. Perkins Award for Excellence in Graduate Student Teaching.

Richard O. Hynes

MIT Reports to the President 1997-98