Titia de Lange, PhD

Cancer is caused by changes in our genes. The genome is protected against such changes by a set of protective proteins that detect damaged DNA and help to repair the damage. Many of the genes that predispose to cancer have recently been found to encode such DNA damage response proteins. Prominent examples are the BRCA1 and BRCA2 gene mutations that cause predisposition to breast and ovarian cancer. Cells lacking BRCA1 or BRCA2 have a diminished ability to repair their DNA, especially during the process of DNA replication that takes place when cells divide. Because of this defect, genetic alterations occur that convert a normal breast or ovary epithelial cell to a cancer cell.

Dr. de Lange's studies are focused on DNA damage response genes and their function in the early stages of breast cancer. The proposed experiments are designed to lead to therapeutic and diagnostic advances with the ultimate goal of preventing breast cancer in high-risk patients by inhibiting the growth of pre-cancerous lesions. Her work has uncovered an unanticipated regulation of a key set of enzymes, the PIKKs. Human cells have several related PIKK enzymes that allow cells to monitor their nutrients and the status of their genome. In human cancer, the pathways controlled by PIKKs are frequently altered and several PIKKs are currently being targeted in cancer therapy.

Dr. de Lange's team has found that the stability of each human PIKK is controlled by Tel2, a protein they initially studied for its suspected role at telomeres. Their data place Tel2 at the nexus of multiple cancer relevant signaling pathways. In the coming year, the researchers will focus their efforts entirely on Tel2. They will continue to explore the underlying mechanism of this new regulator pathway, its biological function, its role in tumorigenesis, and its potential as a target for therapeutic intervention.

Mid-Year Progress Report:
Dr. de Lange's work has uncovered an unanticipated regulation of a key set of enzymes, the PIKKs. Human cells have several related PIKK enzymes that allow cells to monitor their nutrients and the status of their genome. In human cancer, the pathways controlled by PIKKs are frequently altered and several PIKKs are currently being targeted in cancer therapy. They have found that the stability of each human PIKK is controlled by Tel2, a protein the researchers initially studied for its suspected role at telomeres. Their data place Tel2 at the nexus of multiple cancer relevant signaling pathways.

Bio:
A major focus of Dr. de Lange’s research is to isolate the protein components in human telomeres and understand their roles in the cell. Several years ago, this work yielded an unexpected breakthrough, when Dr. de Lange and a collaborator at the University of North Carolina showed that the very tips of human telomeres are not linear, as had been assumed, but instead end in neatly finished loops. The discovery of telomere loops has sparked a reconsideration of many facets of telomere biology, including how these structures are involved in cancer and aging.

Dr. de Lange earned the Dutch equivalent of an M.S. from the University of Amsterdam and the National Institute for Medical Research in London, and a Ph.D. in biochemistry from the University of Amsterdam and The Netherlands Cancer Institute. From 1985 to 1990, she was a postdoctoral fellow in the laboratory of Dr. Harold Varmus at the University of California, San Francisco, where she was one of the first scientists to isolate human telomeres. Dr. de Lange joined The Rockefeller University in 1990 as an Assistant Professor. She was appointed a tenured Professor in 1997 and the Leon Hess Professor in 1999. Her work is focussed on the function of human telomeres and the sources of genomic instability in cancer.

Dr. de Lange is an elected member of the Dutch Royal Academy of Sciences, the European Molecular Biology Organization, the US National Academy of Sciences, and the American Society for Microbiology. Among her awards are the inaugural Paul Marks Prize for Cancer Research from Memorial Sloan-Kettering Cancer Center, the Charlotte Friend Memorial Award of the American Association of Cancer Research, and an honorary doctorate from the University of Utrecht.