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Leif Ellisen, MD, PhDProgram DirectorCenter for Breast Cancer, Massachusetts General Hospital Cancer Center
Professor of MedicineHarvard Medical School
Cancer therapy is being revolutionized through the development of more speciﬁc and less toxic treatment approaches that are collectively known as targeted therapeutics. A 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 laboratory 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 in partnership with the Massachusetts General Hospital Translational Research Laboratory (TRL). Our discoveries in both the basic laboratory and the TRL have led to clinical trials that seek to identify new predictive markers and new therapeutic strategies for breast and other cancers.
Leif W. Ellisen, MD, PhDPrincipal Investigator
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 in partnership with the Massachusetts General Hospital Translational Research Laboratory (TRL). Our discoveries in both the basic laboratory and the TRL are being applied in ongoing clinical trials that seek to identify predictive markers for response to speciﬁc therapeutics for breast and other cancers. 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 p53 tumor suppressor is inactivated in more than 50% of sporadic human cancers, and patients carrying heterozygous germline p53 mutations show striking tumor predisposition. 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. We and others have deﬁned a functional network through which these factors interact in human tumorigenesis. These ﬁndings are likely to explain the observation that p63 is over-expressed in a broad variety of epithelial tumors, particularly squamous cell and breast carcinomas. Our recent work has revealed roles for p63 and p73 in a variety of cancers, including the refractory triple-negative breast cancer subtype which occurs commonly in BRCA1 mutation carriers. In particular, we uncovered a new mechanism by which p63 reprograms chromatin to drive tumor regenerative proliferation. Our success in deﬁning novel functional interactions within the p53 family provides new therapeutic possibilities for these treatment-refractory malignancies.
P53 and TOR-associated metabolic reprogramming in tumorigenesis
Our efforts to identify new pathways regulated by p53 family members have yielded surprising insights into the re-wiring of cellular metabolism that drives carcinogenesis. A central player in this effect is REDD1, a p53- regulated gene we identiﬁed that functions as a critical negative regulator of the mammalian Target of Rapamycin (mTOR) kinase. Most human tumors exhibit abnormalities of p53 and/or mTOR signaling, and our recent studies have demonstrated how REDD1 contributes to autophagy and metabolic homeostasis to suppress growth and metastatic dissemination. We are currently using animal models, in vitro studies, and biochemical approaches to understand key metabolic dependencies of tumors that can be exploited to therapeutic advantage.
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. The Mass General TRL has 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, allowing genotype-directed, personalized selection of patients for trials of promising new drugs.
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, PhDMassachusetts General Hospital Cancer CenterGRJ-90455 Fruit StreetBoston, MA 02114Email: email@example.com
View a list of publications by researchers at the Ellisen Laboratory
Qiao S, Dennis M, Song X, Vadysirisack DD, Salunke D, Nash Z, Yang Z, Liesa M, Yoshioka J, Matsuzawa S, Shirihai OS, Lee RT, Reed JC, Ellisen LW. A REDD1/TXNIP pro-oxidant complex regulates ATG4B activity to control stress-induced autophagy and sustain exercise capacity. Nature Communications. 2015 Apr 28;6:7014.
Isakoff SJ, Mayer EL, He L, Traina TA, Carey LA, Krag K, Rugo H, Liu MC, Stearns V, Come SE, Timms K, Hartman A-R, Borger DR, Finkelstein DM, Garber JE, Ryan PE , Winer EP, Goss PE, Ellisen LW. TBCRC009: A multi-center Phase II clinical trial of platinum monotherapy with biomarker assessment in metastatic triple-negative breast cancer. J Clin Oncol 2015 33:1902-9.
Forster N, Saladi SV, Van Bragt M, Sfondouris ME, Jones FE, Li Z, and Ellisen LW. Basal cell signaling by p63 controls luminal progenitor function and lactation via NRG1. Developmental Cell 2014; 28:147-60.
Ramsey M, Wilson C, Ory B, Rothenberg SM, Faquin W, Mills AA, Ellisen LW. FGFR2 Signaling Underlies p63 Oncogenic Function in Squamous Cell Carcinoma. J Clin Invest 2013; 123:3525-38.
He L, Torres-Lockhart K, Forster N, Ramkrishnan S, Greninger P, Garnett MJ, McDermott U, Rothenberg SM, Benes CH, and Ellisen LW. Mcl-1 and FBW7 control a dominant survival pathway underlying HDAC and Bcl-2 inhibitor synergy in squamous cell carcinoma. Cancer Discovery 2013; 3:324-37.
Ellisen LW. PARP inhibitors in cancer therapy: promise, progress, and puzzles. Cancer Cell. 19:165-7, 2011.
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