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Titia de Lange, PhD
Head, Laboratory of Cell Biology and Genetics
Leon Hess Professor
American Cancer Society Professor
The Rockefeller University
New York, New York
Goal: To improve response to treatment in breast cancers driven by defective BRCA genes.
Impact: Dr. de Lange is conducting studies to understand the mechanisms of resistance to a class of targeted drugs called PARP inhibitors. Her discoveries may lead to the identification of strategies to improve PARP-directed therapy so more patients can benefit from it.
What’s next: She and her team will use advanced molecular and cell biology tools to reveal vulnerabilities of BRCA1-deficient tumors and the mechanisms of resistance to PARP inhibitors.
The BRCA genes are the most commonly mutated genes in hereditary breast cancer, and their mutations lead to faulty DNA damage repair. This defect increases the chance a normal cell will become cancerous. It also makes these cells more vulnerable to certain treatments that cause DNA damage, including a class of drugs called PARP inhibitors. Dr. de Lange is studying why cells that should be sensitive to this type of therapy become resistant, which may reveal ways to prevent this from occurring.
Full Research Summary
Research goal: Understanding the mechanisms of resistance to a class of drugs called PARP inhibitors in breast cancers driven by defective BRCA genes and identifying ways to overcome it.
Impact: BRCA1 is one of the most commonly mutated genes that predisposes women to breast and ovarian cancer. While some patients with this mutation respond to treatment with PARP inhibitors—a type of targeted therapy—others do not. Dr. de Lange and her colleagues are studying the molecular means by which some cancers, caused by errors in the BRCA1-gene, evade treatment with these drugs. Their work may lead to better treatments for patients.
Current investigation: Using an extensive array of molecular tools developed in her laboratory, Dr. de Lange and her team are studying how cells become sensitive to PARP inhibitors and what is needed to maintain this sensitivity so that resistance doesn’t develop.
What she’s learned so far: Dr. de Lange and her colleagues discovered that the loss of a protein called 53BP1 is linked to resistance in BRCA1 cancers treated with PARP inhibitors.
What’s next: The team will continue to investigate additional vulnerabilities of BRCA1-deficient tumors and the mechanisms of resistance to PARP inhibitors.
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.
BCRF Investigator Since
The Bloomingdale's Award