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Othon Iliopoulos, MDClinical Directorvon Hippel-Lindau Disease/Familial Renal Cell Cancer Program, Massachusetts General Hospital Cancer Center
Associate Professor of MedicineHarvard Medical School
The Iliopoulos laboratory works on understanding the biochemical mechanisms of cancer angiogenesis and cancer metabolism in order to identify and validate new targets for anticancer drug development. Cancer cells need oxygen and nutrients to survive, grow and metastasize. To meet these needs, tumor cells activate a sophisticated program known as cancer angiogenesis to stimulate the growth of surrounding blood vessels. In addition, they reshape their metabolic requirement so that they outcompete the normal cells in growth. Our research program focuses on understanding the differences between cancer-induced blood vessels and those that feed normal tissues. We are also exploring the molecular mechanisms through which cancer cells reconﬁgure their metabolism to outcompete normal cells for life-sustaining nutrients; this work has the potential to lead to new targets for drug discovery.
Othon Iliopoulos, MDPrincipal Investigator
Biology of Tumor Angiogenesis and Tumor Metabolism
Our laboratory is interested in tumor angiogenesis and tumor metabolism. Our current studies utilize biochemical, cellular and genetic approaches to dissect the mechanisms by which eukaryotic cells—both normal and neoplastic—sense and respond to hypoxia.
Hypoxia activates several intracellular signaling pathways, leading to secretion of growth and angiogenic factors and to dramatic metabolic changes. Cellular hypoxia activates a family of transcription factors termed hypoxia inducible factors (HIFs). HIF signaling is also directly activated and co-opted by any tumor-initiating mutation. HIF is a powerful regulator of cancer angiogenesis, carbon and lipid metabolism, stem cell proliferation, and tissue differentiation. Inhibition of HIF in preclinical animal models leads to cancer suppression. Levels of HIF expression in human solid and hematologic malignancies have strong prognostic value. Detailed understanding of the molecular events that regulate cancer angiogenesis and metabolism will lead to rational selection of molecular targets for anticancer drug development.
Discovery and Development of Hypoxia Inducible Factor 2a (HIF2a) inhibitors
We have identiﬁed small molecules that repress HIF translation in a highly speciﬁc way by targeting a bifunctional protein that serves either as an mRNA binding protein (i.e., iron regulatory protein 1, or IRP1) or as a cytosolic enzyme of intermediary metabolism (i.e., aconitase 1, ACO1). These molecules are active in vivo and synergistically inhibit all downstream targets of HIF, thereby negatively impacting angiogenesis and tumor metabolism. We are currently using these HIF inhibitors as chemical biology tools to analyze HIF signaling and its effect on metabolism. In parallel studies, we are testing their anticancer function in preclinical experiments.
Modeling Renal Cell Carcinoma in the zebraﬁsh
Zebraﬁsh with homozygous inactivating mutations in vhl gene recapitulate aspects of the human VHL disease, including abnormal proliferation of their kidney epithelium. We are using the zebraﬁsh as a model system to model the diverse pathways that lead to renal cell carcinoma development.
Biomarkers for Early Identiﬁcation of Renal Cell Carcinoma (RCC)
Loss of VHL function and upregulation of HIF activity is a hallmark of human RCC. We combined analysis of HIF-activated genes and signaling pathways speciﬁcally deregulated in RCC with proteomic analysis of patient-derived plasma and tumor samples, and we identiﬁed a set of candidate RCC biomarkers. In addition, we have developed assays to measure the expression of these biomarkers in patient blood. These biomarkers can serve for early identiﬁcation of RCC and as surrogate markers for disease activity in patients enrolled in clinical trials.
Postdoctoral positions are now available in the laboratory of Othon Iliopoulos, MD, at Massachusetts General Hospital Cancer Center and Harvard Medical School. The laboratory studies the regulation of hypoxia signaling and cancer angiogenesis by tumor suppressor genes. We are particularly interested in the Hypoxia-HIF-VHL signaling pathway. We are using cellular, biochemical and genetic approaches to dissect this pathway and to identify and validate molecular targets for drug development. Our laboratory is part of the Massachusetts General Hospital Cancer Center, a state of the art, highly interactive, research facility. PhD and/or MD candidates should be motivated individuals, committed to biomedical research, with experience in molecular biology and/or Drosophila genetics.
Please send CV and contact information for three references to:
Othon Iliopoulos, MD,Massachusetts General Hospital Cancer Center55 Fruit Street GRJ-904BBoston, MA 02114E-mail: firstname.lastname@example.org
View a list of publications by researchers at the Iliopoulos Laboratory
Metelo AM, Noonan HR, Li X, Jin YN, Baker R, Kamentsky L, Zhang Y, van Rooijen E, Shin J, Carpenter AE, Yeh JR, Peterson RT, Iliopoulos O. Treatment of VHL disease pheno-types with small molecule HIF2a inhibitors. Journal Clinical Investigation 2015; 125 (5):1987-97.
Gameiro PA, Yang J, Metelo AM, Pérez-Carro R, Baker R, Wang Z, Arreola A, Rathmell WK, Olumi A, López-Larrubia P, Stephanopoulos G and Iliopoulos O. HIF mediated reductive carboxylation occurs in vivo through regulation of citrate levels and sensitizes VHL-deﬁcient cells to glutamine deprivation. Cell Metabolism. 2013;17 (3): 372-385.
Laviolette LA, Wilson J, Koller J, Neil C, Hulick P, Karger B, Teh BT, Iliopoulos O. Human Folliculin delays cell cycle progression through late S and G2/M-phases: effect of phosphorylation and tumor associated mutations. PLoS ONE. 2013 Jul 11;8(7):e66775.
Metallo CM, Gameiro PA, Bell EL, Mattaini KR, Yang J, Hiller K, Jewell CM, Zachary R. Johnson JR, Irvine DJ, Guarente G, Kelleher JK, Vander Heiden MG, Iliopoulos O* and Gregory Stephanopoulos*. Reductive glutamine metabolism by IDH1 mediates lipogenesis under hypoxia. Nature. 481 (7381):380-4, 2011 Nov 20.
Zimmer M, Lamb J, Ebert BL, Lynch M, Neil C, Schmidt E, Golub T, Iliopoulos O. The Connectivity Map links Iron Response Protein-1 (IRP1)-mediated inhibition of HIF2a translation to the anti-inﬂammatory 15-deoxy-Δ12,14-Prostaglandin J2. Cancer Research. 70(8):3071–9. 2010 Apr 15.
Hulick P, Zimmer M, Margulis V, Skates S, Hamel M, Dahl D, Michaelson D, Liebermann T, Signoretti S, Carney W, Wood C, Iliopoulos O. Blood levels of carbonic anhydrase 9 correlate with clear cell carcinoma activity. Clinical Proteomics. 5(1):37-45. 2009.
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