J. Dirk Iglehart, MD
Anne E. Dyson Professor of Women's Cancers and Surgery, Harvard Medical School
Dana-Farber Cancer Institute
Brigham and Women's Hospital
2013-2014 BCRF Project:
(The Neil and Jane Golub and Price Chopper SuperMarkets Award)
Co-Investigators: Andrea Richardson, MD and Zhigang Charles Wang, MD, Brigham and Women's Hospital, Harvard Medical School, Boston
The research team at the Brigham and Women’s Hospital and Dana-Farber Cancer Institute is a cross-discipline collaboration of a surgeon oncologist and two pathologists who are both PhD-level human geneticists. The team has investigated the genetics of breast cancer for the past ten years and has contributed important observations, made possible by BCRF funding. Last year, the Brigham/DCFI team investigated the role of a class of regulatory molecules called micro-RNAs, and uncovered interesting effects of these molecules on better known breast cancer genes and proteins, including the BRCA1 gene that causes hereditary breast cancer. The Brigham/DFCI group has also focused on the consequences of impaired repair of cancer DNA, or the cancer genome. Faulty repair leads to genome instability and to regions of chromosomal losses and gains. The result of genetic instability can be cancer, and this seems to be the reason why women with an inherited BRCA1 or BRCA2 mutation get cancer, they are missing important steps in DNA repair. However, faulty repair in the cancer cell can be an Achilles’ heel, and cancers with faulty repair may be more sensitive to particular types of chemotherapy, and to new agents that actually target and disable aspects of DNA repair.
This coming year, the Brigham/Dana-Farber investigators will concentrate on this vulnerability in DNA repair, using new drug combinations, and novel technologies in the laboratory. This team has always been interested in triple negative breast cancer, characterized by genetic instability. Its disorganized genetic code is probably due to a defect in triple negative breast cancer’s ability to repair its own DNA and restore order to its genome. The researchers propose three research approaches to triple negative diease: The first is to design a better combination of chemotherapy for treatment, taking advantage of the DNA repair vulnerability. The second is to look at predictors of response to chemotherapy, particularly in disease caused by inherited genes. The third aim is to look at genetic features of the actual repair of DNA damage cause by cisplatinum chemotherapy, looking for signatures of faulty repair. A number of important scientific papers have been published by this group and credit BCRF support.
This team has team wondered whether the degree of instability and genetic unsteadiness displayed by triple-negative cancers might itself be a target of treatment. They pioneered the use of chemotherapy with a drug called cisplatin in triple-negative breast cancer, based upon this defect in keeping DNA free from damage. In their current work, they are testing other drugs that can be used in combination with cisplatin chemotherapy for the treatment of triple-negative breast cancer. These experiments uncovered unexpected degrees of synergy between combinations of cisplatin and other drugs that target important participants in DNA damage repair. During the remainder of this year, they will continue to develop these drug combinations, and are planning early-phase clinical trials with their BCRF collaborators at the Dana-Farber. In addition to developing new drug combinations, they also are seeking ways to predict which triple-negative tumors will respond to cisplatin chemotherapy. These predictors or “bio-markers” of treatment response require use of the resesarchers’ extensive tissue bank of breast cancer specimens and active collaboration with physicians, including many BCRF investigators, who are doing innovative clinical trials for women with triple-negative breast cancer.
Dirk Iglehart is Anne E. Dyson Professor of Women's Cancers and Surgery, at Brigham and Women's Hospital/Dana-Farber Cancer Institute. After graduation from Harvard Medical School, he went on to do his surgical residency at Duke University Medical Center in Durham, North Carolina. In 1999, he was recruited to Harvard Medical School where he maintains both an active clinical practice as well as a laboratory which studies the fundamental issues of breast cancer. In October of 2000, Dr. Iglehart became the Director of the Dana-Farber/Harvard Specialized Program of Research Excellence (SPORE) in breast cancer. SPOREs are large National Cancer Institute program project grants which emphasize translational or bench-to-bedside research.