Louise Foote Pfeiffer Professor of Cell Biology
Chair, Department of Cell Biology
Harvard Medical School
Dr. Brugge’s team completed studies of a complex of proteins that suppress tumor cell invasion and published a report in Cancer Cell describing how this complex functions and how changes in the expression of complex components can provoke more aggressive invasive behavior in human tumors. They also found that this protein is a significant predictor of poor outcome in human breast cancer patients.
In collaboration with fellow BCRF grantee, Dr. Myles Brown (Dana-Farber Cancer Institute), Dr. Brugge identified the functional activities of a protein, PDEF, which is one of the most highly expressed protein in ER-positive breast cancers. These studies show that PDEF can drive differentiation of breast cells and that it is critical for survival of estrogen receptor-positive (ER+) breast tumor cells.
In a separate project, since fall 2012 Dr. Brugge’s team has carried out multiple studies designed to define adaptive responses to targeted treatments for breast cancer. These adaptive responses can significantly decrease the sensitivity of the tumor cells to the targeted therapies and allow maintenance of drug resistant cell populations. Dr. Brugge’s previous studies identified specific niches within the tumor that specifically undergo these responses. Currently, this team has expanded their analysis of the adaptive response to HER2-targeted therapies in vivo. They have also extended their DCIS model to include another HER+ breast tumor cell line, evaluated the response of these two cell lines and others to lapatinib within invasive tumors, and continued to explore conditions to abrogating drug resistance in protective niches by treated with a combination of a HER2-targeted drug and an inhibitor of a critical cell survival protein.
In future studies, Dr. Brugge will further define the nature of the adaptive responses in carcinoma-in-situ and invasive HER1+ tumors and will test combination therapies that abrogate the adaptive response and enhance the efficacy of HER+ therapies.
Tumors evolve through expansion of individual tumor cells, genetic diversification, and selection of the most ‘fit’ tumor cells. This process generates considerable genetic diversity among tumor cell populations within individual tumors. In addition, individual tumor cells can undergo distinct non-genetic alterations that can have profound effects on tumor pathogenesis and drug sensitivity, the latter presenting one of the most significant challenges in cancer treatment. Dr. Brugge’s laboratory has initiated a novel approach to track millions of individual tumor cells following transplantation into laboratory models by tagging each tumor cell with a unique DNA sequence that is easily quantified in primary tumors and metastatic outgrowths. This approach provides an unprecedented opportunity to track the fate of millions of tumor cells or specific subsets of tumor cells over time after transplantation, and after treatment with cancer therapeutics. During the first six months of this project the researchers have developed conditions for the growth of human-derived tumor cells in culture and established four human triple-negative tumor models for the proposed studies as well as performed a pilot experiment using an established triple-negative cell line in order to optimize all the protocols. These studies promise to provide valuable information on tumor cell population dynamics in vivo, which has not been feasible to date, and to identify and isolate subpopulations low sensitivity to therapeutic agents.
A second project led by Dr. Brugge is focused on drug resistance. Studies from her laboratory have provided evidence that tumor cells in certain ‘niches’ are protected HER2- targeted therapies. During the last six months the Brugge laboratory has found that treatment of xenografts of HER2+ human tumors in laboratory models with a combination of the HER2-targeted drug lapatinib and a dual PI3K/mTOR inhibitor resulted in superior blockade of HER2-activated pathways and strongly enhanced tumor cell death overall, as well as the death of the ‘niche’ associated cells that were protected from HER2+ therapy alone. These data show promise to eliminate cells resistant to HER2 therapies and thus reduce the chances of relapse. In addition, the researchers have found a striking difference in treatment responses to HER2 therapy in tumors within different tumor microenvironments and are developing strategies to identify the factors that confer resistance in the protected environments.
Joan Brugge joined the faculty of the Department of Cell Biology at Harvard Medical School in July 1997 and became the Chair of this department in 2004. A graduate of Northwestern University, she did her graduate work at the Baylor College of Medicine, completing her PhD in 1975. During her postdoctoral training at the University of Colorado she isolated the protein coded for the viral and cellular forms of the src gene. These proteins were the first viral/cellular oncogene products to be identified, and the study of the normal and oncogenic forms of this gene product has served as a model system to investigate cellular processes that regulate normal growth and the mechanisms involved in tumor formation.
In the 15 years since that discovery, Dr. Brugge has held full professorships at the State University of New York, Stony Brook, and the University of Pennsylvania, where she was also named as an investigator at the Howard Hughes Medical Institute. In 1992 Dr. Brugge left academia to help found a new company, ARIAD, to focus on research aimed at developing new drugs for asthma and allergy, cystic fibrosis, cancer, and other diseases that result from cellular regulation gone awry.
Dr. Brugge has received several awards recognizing her scientific accomplishments including an NIH Merit Award, an American Cancer Society Research Professorship and the Senior Career Recognition Award from the American Society of Cell Biology, and she has been elected to the American Academy of Arts and Sciences, the National Academy of Sciences and the Institute of Medicine.