Leif Ellisen, MD, PhD
Center for Breast Cancer, Massachusetts General Hospital Cancer Center
Associate Professor of Medicine
Harvard Medical School
Research SummaryCancer therapy is being revolutionized through the development of more specific and less toxic treatment approaches that are collectively known as targeted therapeutics. Key to the successful application of targeted cancer therapy is the identification of specific genetic abnormalities within tumor cells that are not present in normal tissues. The Ellisen lab is broadly interested in identifying these genetic abnormalities, understanding how they influence the biology of cancer cells, and discovering how that biology can inform the selection of the most effective therapy for each patient. We address these questions through basic research studies of key tumor-cell signaling pathways and through genetic analysis of patient tumor samples conducted by our companion laboratory, the Massachusetts General Hospital Translational Research Laboratory. Our discoveries in both the basic laboratory and the Translational Research Laboratory have already been translated to clinical trials that seek to identify new predictive markers and new therapeutic strategies for many different cancers.
Leif W. Ellisen, MD, PhD
Our group is broadly interested in how genetic abnormalities within cancer cells influence their biology and how that biology can, in turn, be exploited to therapeutic advantage. We address these questions through basic research studies of key tumor cell signaling pathways including p53, mTOR, and BRCA1/2. This work is complemented by genetic analysis of patient tumor samples conducted through our companion laboratory, the Massachusetts General Hospital Translational Research Laboratory. Finally, our discoveries in both the basic laboratory and the Translational Research Laboratory are being applied in ongoing clinical trials which seek to identify predictive markers for response to specific therapeutic agents. Our ability to work at the interface of basic tumor biology and therapeutic application is strongly supported by our network of collaborators and by the research and clinical infrastructure of the Mass General Cancer Center.
The p53 network in cancer biology and therapy
The essential role of the p53 tumor suppressor is evidenced by its inactivation in more than 50% of sporadic human cancers and by the striking tumor predisposition of patients carrying heterozygous germ line p53 mutations. P53 encodes a transcription factor that functions as a key nodal point for integrating cellular responses to DNA damage. As such, p53 regulates genes involved in diverse cellular processes including cell cycle progression, apoptosis and angiogenesis. The identification of two p53-related genes, p63 and p73, provided a new paradigm in the study of p53. Recent work by our group and others has defined a functional network through which these factors interact in human tumorigenesis. Our findings are likely to explain the observation that p63 is over-expressed in a broad variety of epithelial tumors, particularly squamous cell carcinomas. Our recent work has also defined roles for p63 and p73 in breast, ovarian and squamous cancers, including the refractory triple-negative breast cancer subtype which occurs commonly in BRCA1 mutation carriers. Our success in defining novel functional interactions within the p53 family provides new therapeutic possibilities for these treatment-refractory malignancies. We are currently carrying out high-throughput approaches to identify specific therapeutic targets within the critical pathways we have uncovered.
TOR signaling and the p53-regulated stress response
One gene to emerge from our efforts to identify new pathways regulated by p53 family members is REDD1, which is induced by p53 following DNA damage and by other factors in response to diverse stress stimuli including hypoxia and energy stress. REDD1 functions as a critical negative regulator of the Target of Rapamycin (TOR) kinase by modulating the activity of the tuberous sclerosis tumor suppressor complex. Most human tumors exhibit abnormalities of p53 and/or TOR signaling, and indeed our biochemical and in vivo studies have demonstrated that REDD1 itself functions in a novel tumor suppressor pathway. We are currently using animal models, in vitro studies, and biochemical approaches to understand the mechanisms of REDD1-mediated tumor suppression.
Tumor genotyping to drive personalized cancer therapy
Specific somatic genetic abnormalities—including gene mutation, rearrangement and amplification—are acquired by nascent tumor cells and drive cancer pathogenesis. Activation of diverse oncogenes (e.g., RAS, RAF, EGFR) through such somatic mutation not only causes cancer, but is now known to be an important determinant of the clinical response to targeted therapeutics. Until recently, identifying such abnormalities was restricted to research settings as the technologies required for routine, high-performance tumor genotyping were not available. At the Mass General Translational Research Laboratory, we have developed and validated high-throughput clinical diagnostic platforms for broad-based tumor genetic analysis. The availability of tumor genotyping for our large cancer patient population is accelerating the clinical trials process and is providing remarkable new opportunities for translational research.
Postdoctoral Research Fellow (1)
One Postdoctoral Research Fellow position is immediately available in the Jackson 9 Laboratories to study the role of p53 family members in human tumorigenesis. The candidate must have recently received a PhD degree in the biological sciences, and be highly motivated and well versed in basic molecular biology and biochemical techniques. The Fellow will have simultaneous academic appointments at the Massachusetts General Hospital and Harvard Medical School. We are using a number of genetic and biochemical approaches, including analysis of gene expression profiling and mouse models, to characterize the cellular pathways activated by p53, the most commonly mutated gene in human cancer. Related to these studies is our work on the p53 family member p63, which plays important roles in both human tumorigenesis and human development. We have recently identified novel downstream targets of p53 and p63, characterization of which will give new insights and provide new diagnostic and therapeutic approaches to human cancer. The position provides a rich intellectual environment within a group of young investigators, with full integration into the large research communities of the Massachusetts General Hospital and Harvard.
Please email a brief cover letter and CV to:
Leif W. Ellisen, MD, PhD
Massachusetts General Hospital Cancer Center
55 Fruit Street
Boston, MA 02114
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