Titia de Lange, PhD
New York, New York
Leon Hess Professor
Director, Anderson Center for Cancer Research
The Rockefeller University
New York, New York
Understanding how cancer cells survive DNA damage to continue growing and resist therapies.
Enduring DNA damage is critical for cancer cells to survive. They divide so rapidly that it can be a messy process, resulting in mutations or genomic events that would kill a non-cancerous cell. Cancer cells, especially breast and ovarian cancers, can also harbor mutations in genes that are important for DNA repair—like the BRCA genes. This predisposes cells to become cancerous in the first place, but also makes them vulnerable to further DNA damage. Cancer cells that harbor this defect, however, may utilize other DNA repair processes, which allows for their growth and resistance to many cancer therapies. Dr. de Lange and her team study these survival mechanisms to help identify new vulnerabilities to target with therapy, or new strategies for overcoming drug resistance.
Dr. de Lange and her team identified a protein complex that is critical for the effectiveness of PARP inhibitors in BRCA1-deficient cells. Using an extensive array of molecular tools, the team is testing how this complex interacts with other DNA repair proteins to enable PARP inhibitors to kill breast cancer cells. And in the process of working on this project, they also identified another gene that may be important for normal BRCA1 function.
The team will continue to investigate the complex involved in PARP inhibitor response and pursue their findings of a gene that promotes BRCA1 stability and normal function. They are also studying how cancer cells add new telomeres—protective caps that are needed on the ends of DNA—on the ends of broken chromosomes. This is vital for the survival of cancer cells, but how cancer cells generate telomeres on broken chromosomes is unknown: do they copy existing telomeres from other, intact chromosomes, or do they need telomerases to form brand new telomeres? Understanding this could lead to a new therapeutic strategy that interferes with telomere formation in cancer.
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. 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. She was appointed a tenured Professor in 1997 and the Leon Hess Professor in 1999.
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.
The Macy's Award
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