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Research at Mass General
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 treatment of Renal Cell Carcinoma (RCC).
Cancer cells transform their metabolism to adapt to the needs of fast growth and to compete with the surrounding normal cells for nutrients and oxygen. In addition to a reprogrammed metabolism, cancer cells stimulate the growth of new blood vessels that bring blood to them, a phenomenon known for many years as “cancer angiogenesis”. The overall goal of my laboratory is to understand the main mechanisms underlying the reprogramming of cancer cell metabolism and cancer angiogenesis and to develop mechanism-based strategies for selectively killing cancer cells.
Othon Iliopoulos, MDPrincipal Investigator
Discovery and Validation of Therapeutic Targets for Treatment of Renal Cell Carcinoma
My laboratory uses Renal Cell Carcinoma (RCC) as a disease model to study cancer metabolism and angiogenesis. The overwhelming majority of RCC tumors (more than 90%) lack the VHL tumor suppressor protein. The main function of this protein in the cells is to keep Hypoxia Inducible Factor 2 (HIF2a) under physiologic control; VHL allows the expression of HIF2a only when the cells lack nutrients or the oxygen level drops within a cell (hypoxia). HIF2a is a protein that binds DNA and activates the expression of many genes that interfere with cancer angiogenesis and metabolism. In other words, HIF2a is a “master regulator” of cancer metabolism and angiogenesis. RCCs that lack VHL have continuous expression of HIF2a, independently of the oxygen or nutrient levels within the cell. This inappropriate activation turns HIF2a into an oncogenic “driver” of RCC tumors. In addition to mutations in the VHL gene, mutations in other metabolic enzymes such Succinate Dehydrogenase (SDH) and Fumarate Hydratase (FH) are also linked to the development of RCC. Taken together, these data suggest that the initiation and progression of RCCs depend on metabolic and angiogenic reprogramming. 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 for treatment of Renal Cell Carcinoma and other HIF2a-dependent cancers
We screened libraries of chemical compounds and discovered chemical molecules that significantly and specifically decrease the expression of HIF2a (Zimmer M. et al. Molecular Cell 2008; 32(6): 838-48). We used these HIF2a inhibitors as chemical biology probes and we discovered that they suppress the expression of HIF2a by activating a cellular protein that senses iron levels. We thus proved a crosstalk between the iron and oxygen sensing mechanisms within the cell. Next we studied the therapeutic potential of these HIF2a inhibitors in two animal models (zebrafish and mice). We demonstrated that the HIF2a inhibitors we discovered are “active” and that they reverse the consequences of VHL protein loss (Metelo AM. Journal Clinical Investigation 2015; 125(5): 1987-97). Our chemical HIF2a inhibitors are very promising agents for treating RCC.
Targeting the metabolic reprogramming of RCC and HIF2a expressing tumors; from the lab to the bedside
We used modern methods of studying metabolism to show that hypoxic cells use glutamine as a carbon source for anabolism. Moreover, we described for the first time in mammalian cells a novel metabolic pathway that was previously only detected in bacteria. Specifically, we showed that low oxygen levels or HIF2a expression reprogrammed cells to use glutamine in a “reverse” TCA cycle to produce the metabolites required for anabolic reactions, a process called Reductive Carboxylation. The Reductive Carboxylation pathway departs from the classic TCA cycle paradigm and these observations provided insights into a mechanism by which hypoxic and HIF2a expressing cancer cells compensate for the Warburg phenomenon (Metallo et al. Nature 2012; 481(7381): 380-4). We delineated the mechanism driving Reductive Carboxylation and we also showed that reductive carboxylation does not only happen in cultured cells, but can also be detected in human RCC tumors growing as xenografts in mice. We therefore provided for the first time in vivo evidence for the utilization of glutamine in tumors through reductive carboxylation (Gameiro et al. Cell Metabolism 2013; 17(3): 372-385).
Moreover, we brought these fundamental observations of my lab on glutamine metabolism and its targeting in RCC cells from the laboratory to the clinic. We initiated a Phase 1 trial with Glutaminase 1 (GLS1) inhibitors for patients with RCC and triple negative breast cancer.
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.
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: email@example.com
View a list of publications by researchers at the Iliopoulos Laboratory
Noonan HR, Metelo AM, Kamei CN, Peterson RT, Drummond IA, Iliopoulos O. Loss of vhl in the zebrafish pronephros recapitulates early stages of human clear cell renal cell carcinoma. Dis Model Mech. 2016; 9(8):873-84.
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.
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