Titia de Lange, PhD

Cancer is caused by changes in our genes. The genome is protected against such changes by a set of 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 protective DNA damage response proteins, and most cancer cells have dramatically rearranged genomes. The regulation of genome stability is therefore a key issue in tumor biology. Central to the control of genome integrity is a family of protein kinases, referred to as PIKKs, that alert cells to damage in their DNA and facilitate DNA repair.

Dr. de Lange's laboratory has discovered a previously unknown regulatory pathway that is required for the function of all PIKKs and are studying how this regulation can be explored in the cancer clinic. Their work has uncovered an unanticipated regulation of the PIKKs. Human cells have six PIKK enzymes that inform cells of the nutrients available, the status of their genome, and mistakes in gene expression. In human cancer, the pathways controlled by PIKKs are frequently altered and several PIKKs are currently being targeted in cancer therapy.

The de Lange laboratory has found that the stability of each human PIKK is controlled by Tel2, a protein they initially studied for its suspected role at telomeres. This data places Tel2 at the nexus of multiple cancer-relevant signaling pathways. In the coming year, the scientists plan to dissect the mechanism by which Tel2 regulates the PIKK enzymes and test whether inhibition of Tel2 has utility in cancer treatment.

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.