Titia de Lange, PhD
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 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 CST/Pol⍺/primase (CPP), that is critical for the effectiveness of PARP inhibitors in BRCA1-deficient cells. Using an extensive array of molecular tools, the team determined how CPP interacts with other DNA repair proteins and enables PARP inhibitors to kill breast cancer cells—it prevents the formation of what is known as a 3’ overhang in the broken DNA, which would otherwise initiate a DNA repair process that circumvents the action of PARP inhibitors. In addition, the team discovered a previously unanticipated role for a protein known as CRL4WDR70, in the regulation of generation of the DNA repair proteins BRCA1 and BRCA2. The knowledge built by the de Lange team is vital to furthering our understanding of how to effectively treat breast cancers with DNA repair deficiencies, especially those driven by mutations in the BRCA gene.
The team is also studying how cancer cells add new telomeres on the ends of broken chromosomes. Telomeres serve as protective caps on the ends of DNA. 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 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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