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Research at Mass General
Read the Iliopoulos Lab 2017-2018 Annual Report
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 the main mechanisms underlying the reprogramming of cancer cell metabolism and cancer angiogenesis with the goal to develop mechanism-based strategies for selectively killing cancer cells. We use Renal Cell Carcinoma (RCC) as a model disease of altered cancer metabolism and angiogenesis mechanisms. 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 laboratory identifies and validates therapeutic targets that disrupt these processes.
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). Recently we showed that inhibition of Glutaminase 1 (GLS1) decreases significantly the intracellular pyrimidines and results in DNA replication stress in HIF-hypoxia driven cancer cells. Treatment of cancer cells with GLS1 and PARP inhibitors resulted in dramatic suppression of RCC in xenograft models (J Clin Invest. 2017; 127(5): 1631-1645).
Moreover, we brought these fundamental observations of my laboratory 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 cancers nationwide. The results were very encouraging. We are now opening, based on compelling preclinical data, a new clinical trial of GLS1 inhibitor CB-839 and PARP inhibitor combination treatment for patients with RCC, prostate, triple negative and ovarian 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.
There is a post-doctoral position available in the laboratory of Othon Iliopoulos, MD, PhD at the Massachusetts General Hospital Cancer Center and Harvard Medical School. We study the molecular and metabolic effects of hypoxia on cancer cell metabolism and signaling, with a particular clinical interest in renal cell, ovarian and prostate cancer. The goal is to identify and validate novel strategies to target cancer metabolism. Specific projects related to this goal include identification of the signaling and epigenetic events induced by altered tumor metabolism, the role of VHL-HIF in tumor growth and metastasis, the molecular function of tumor suppressor genes mutated in renal cancer (such as VHL, FLCN, BAP1) and the role of driver mutations in the development of human hemangioblastomas.
The ideal candidate should have experience with molecular and/or metabolic techniques. Standard techniques in the lab include cell and molecular biology techniques. Knowledge of single-cell RNA sequencing and background in zebrafish and mouse models is advantageous but not required.
To apply, please send an email with CV and cover letter to: firstname.lastname@example.org
View a list of publications by researchers at the Iliopoulos Laboratory
Okazaki A, Gameiro PA, Christodoulou D, Laviollette L, Schneider M, Chaves F, Stemmer-Rachamimov A, Yazinski SA, Lee R, Stephanopoulos G, Zou L, Iliopoulos O. Glutaminase and poly(ADP-ribose) polymerase inhibitors suppress pyrimidine synthesis and VHL-deficient renal cancers. J Clin Invest. 2017; 127(5): 1631-1645. (Research Highlights “Targeting metabolism in RCC” in Nature Reviews Nephrology. 13, 320 (2017).
Laviolette LA, Mermoud J, Calvo IA, Olson N, Boukhali M, Steinlein OK, Roider E, Sattler EC, Huang D, Teh BT, Motamedi M, Haas W, Iliopoulos O. Negative regulation of EGFR signalling by the human folliculin tumour suppressor protein. Nat Commun. 2017; 28;8: 15866.
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.
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, Ebert BL, Neil C, Brenner K, Papaioannou I, Melas A, Tolliday N, Lamb J, Pantopoulos K, Golub T, Iliopoulos O. Small-molecule inhibitors of HIF-2a translation link its 5'UTR iron-responsive element to oxygen sensing. Molecular Cell. 2008; 32(6): 838-48.
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