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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
- Seeking to improve response to treatment in breast cancers driven by defective BRCA genes.
- Laboratory studies are ongoing to understand resistance to a class of targeted drugs called PARP inhibitors and identify strategies to improve PARP-directed therapy.
- These studies will help to identify new combination approaches and treatment options for patients with triple negative breast cancer.
The BRCA genes are the most commonly mutated genes in hereditary breast cancer. Mutations in BRCA affect how the cell repairs DNA damage and while 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. One type of drug that falls into this class is called PARP inhibitors (PARPi) and the first PARPi were approved this year for advanced breast cancers with BRCA mutations. Dr. de Lange is conducting studies to understand how cells that should be sensitive to PARPi become resistant so that more patients can benefit from this targeted therapy.
Full Research Summary
BRCA1 is one of the most commonly mutated genes that predisposes women to breast and ovarian cancer. The function of BRCA1 is to maintain the integrity of DNA, which undergoes a wide variety of damaging events in every cell, every day. Loss or mutation of BRCA1 leads to faulty repair of broken DNA ends and creates changes that can promote cancer progression.
On the other hand, the inability of BRCA1-deficient cancer cells to repair DNA damage makes them more vulnerable to a class of drugs called PARP inhibitors (PARPi). PARPi have shown promise in the clinic for the treatment of BRCA1-deficient cancers and other aggressive forms of breast cancers with defects in DNA repair including many triple negative breast cancers.
Dr. de Lange's BCRF-supported research focuses on understanding the basic biological mechanisms by which PARPi kill breast cancer cells that are defective in BRCA1. Using the extensive battery of molecular tools developed in her laboratory, she is investigating exactly how cells become sensitive to PARPi and what is needed to maintain this sensitivity so that resistance does not arise.
In the last year, the team found a completely new mechanism by which PARPi kill BRCA1 breast cancer cells. The group has shown that a system that repairs and protect chromosome tips also works at the DNA damage sites created by PARPi. The team is thus beginning to understand how resistance to PARPi happens.
This year, they plan to investigate two critical enzymes involved in this process, TREX1 and APOBEC3B, and will determine their exact roles in tumor genome changes.
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