The Rockefeller University New York, New York
Leon Hess Professor Director, Anderson Center for Cancer Research
Understanding how cancer cells survive DNA damage to continue growing and resist therapies.
Cancer cells walk a fine line when it comes to DNA damage. An abnormal amount, caused by defects in DNA repair genes like BRCA, can result in mutations that drive cancer development and growth. But excessive DNA damage, brought on by therapies like PARP inhibitors, results in cancer cell death. Tumors adapt to DNA damage by activating alternate DNA repair processes, which not only enable their survival but allow them to develop resistance to some cancer therapies. Dr. de Lange and her team study these survival mechanisms to help identify new vulnerabilities to target with therapy and new strategies for overcoming drug resistance.
Dr. de Lange and her team identified a protein complex, known as CPP, that is critical for the effectiveness of PARP inhibitors in BRCA1-deficient cells. Using an extensive array of molecular tools, the team determined the structure and binding properties of CPP. This allows them to understand key mechanistic details of its activities – they found it interacts with other DNA repair proteins facilitating the anti-cancer activity of PARP inhibitors.
The team has uncovered a new function of telomerase, an enzyme that normally helps protect the ends of chromosomes, that may play a role in tumor progression. “Neotelomere” formation at the end of DNA breaks may stabilize genomes with many broken chromosomes that are found in early breast cancer development.
The team will continue to identify and exploit genomic instabilities and vulnerabilities in breast cancer cells. They will evaluate the impact of inhibiting telomerase activity and use new techniques to examine another telomere maintenance enzyme that the team has recently identified. Like telomerase, this enzyme is needed to counteract the loss of DNA with each cell division. Understanding these critical mechanisms could lead to a new therapeutic strategy that interferes with telomere formation in cancer and thus, tumor cell survival.
Titia de Lange, PhD is the Leon Hess Professor and director of the Anderson Center for Cancer Research at The Rockefeller University. From 1985 to 1990, Dr. de Lange was a postdoctoral fellow in the laboratory of Dr. Harold Varmus at UCSF, 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 and was appointed to tenured Professor in 1997. 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 UNC 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 is an elected member of the Dutch Royal Academy of Sciences, the European Molecular Biology Organization, the US National Academy of Sciences, the Institute of Medicine, and the American Academy for Arts and Sciences. Among her awards are the inaugural Paul Marks Prize for Cancer Research from Memorial Sloan Kettering Cancer Center, the 2011 Vilcek Prize for Biomedical Science, and the Heineken Prize from the Royal Dutch Academy for Arts and Sciences. In 2013, she was one of the 11 inaugural recipients of the Breakthrough Prize in Life Sciences; she also received the 2014 Canada Gairdner International Award.
2003
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