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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 has identified a protein complex called CPP that is important in the cell killing effects of a class of targeted drugs called PARP inhibitors, an approved therapy for breast and ovarian cancers caused by mutations in the BRCA genes. Understanding how PARP inhibitors work is an important step in identifying the causes of resistance to these therapies.
What’s next: She and her team will use advanced molecular and cell biology tools to further explore the relationship of CPP to BRCA to gain insight into response 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 what makes cells sensitive to PARP inhibitors and why cells 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 identified a protein complex, CPP, that is critical for PARP inhibitors to have their lethal effect on BRCA1-deficient cells. Understanding the molecular means by which BRCA1-deficient cancers are susceptible to PARP inhibitors or can develop resistance to them may lead to better treatments for patients.
Current investigation: Using an extensive array of molecular tools developed in her laboratory, Dr. de Lange is testing how CPP interacts with DNA to enable PARP inhibitors to kill breast cancer cells. She and her team are also investigating the origins of chromothripsis, a frequent phenomenon seen in breast and other cancers in which a chromosome is fragmented and repaired incorrectly.
What she’s learned so far: Dr. de Lange and her colleagues discovered that the protein complex CPP is responsible for repair errors and lethality to breast cancer cells treated with PARP inhibitors.
What’s next: The team will continue to investigate vulnerabilities of BRCA1-deficient tumors, the mechanisms of resistance to PARP inhibitors, and other cancer-associated DNA repair defects.
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