Titia de Lange, PhD

Cancer genome sequencing efforts have illuminated the horrific genomic alterations underlying human breast cancer. Over the past years, Dr. de Lange's team has provided evidence that the gradual loss of telomere function and the resulting telomere crisis can explain much of the genome instability in the early stages of breast cancer development. Their current efforts are focused on developing a molecular signature for telomere crisis, allowing them to identify human tumors that have experienced this type of genome instability in their proliferative history so that they can harness the therapeutic and diagnostic potential associated with this aspect of tumorigenesis.

Mid-year Progress: As part of a second long-term project supported by the BCRF, Dr. de Lange's team has recently uncovered a role for the Rif1 gene in BRCA1-deficient breast cancer. Their work reveals that Rif1 is responsible for the maximal sensitivity of BRCA1-deficient breast cancer to the PARP1 inhibitor class of drugs that are currently studied in the clinic. They have shown that Rif1 acts by altering the processing of double-stranded breaks, blocking nucleases that prepare DNA ends for repair by homologous recombination.

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 a master's of science degree from the University of Amsterdam and the National Institute for Medical Research in London, and a PhD 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, an honorary doctorate from the University of Utrecht, and the 2011 Vilcek Prize for Biomedical Science.