The research lab of Mircea Ivan MD, PhD is studying the metabolic branches of the hypoxic response and how they can be exploited for synergistic anticancer combinations in solid tumors (with emphasis on brain cancer).
The laboratory is performing therapeutic targeting of brain cancer metabolism using combinations of specific metabolic inhibitors and antiangiogenic agents. The overall goal is to better understand an exploit the vulnerabilities generated by the tumor microenvironment.
The Ivan Lab is also dissecting the role of specific noncoding RNAs generated by the miR210HG and miR193BHG loci as feedback modifiers of the hypoxic response.
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In 2007 the Ivan Lab was the first to identify microRNAs induced by decreased oxygen tension, including miR-210, now widely recognized as the prototypical “hypoxia-miR”. Ongoing studies of hypoxia-regulated noncoding RNA aim to provide a deeper understanding of how oxygen deprivation impacts cell metabolism and growth in normal physiology and cancer.
In parallel, the laboratory is developing new combinatorial therapeutic approaches based on rational interference with tumor metabolism, with a focus on high-grade glioma. In 2013 the lab generated proof of concept showing that blockade of pyruvate dehydrogenase kinase using dichloroacetate (DCA) significantly increases the efficacy of antiangiogenic agents in xenografts.
Research Funding
Sterol Biosynthesis Regulation by Noncoding RNAs
Role: PI
“Overcoming Resistance to Antiangiogenic Drugs in Glioblastoma Multiforme by Interfering with Tumor Metabolism.”
Role: PI with K. Pollok
R21 CA213977-01A1: Epigenetic modulation of SEC24D and circulating miR-605 in renal cell carcinoma.
Role: Co-investigator
1R01CA167291-01A1: Novel Role of Ref-1 in Pancreatic Cancer Etiology and Progression.
Role: Co-investigator
1R01AR067210-01: Osteocyte apoptosis and regulation of bone resorption with aging.
Role: Co-investigator
Functional and Mechanistic Analysis of Mesenchymal Stem Cell Secretome to Ameliorate Ischemic Damage of Rodent Hearts in situ and Human Myocardium-on-a-Chip.
Role: Co-investigator
Recent Publications
Ivan M, Kaelin WG Jr. The EGLN-HIF O2 Sensing System: Multiple Inputs and Feedbacks. Mol Cell. 2017 Jun 15;66(6):772-779. doi: 10.1016/j.molcel.2017.06.002
Brady LK, Wang H, Radens CM, Bi Y, Radovich M, Maity A, Ivan C, Ivan M, Barash Y, Koumenis C. Transcriptome Analysis of Hypoxic Cancer Cells Uncovers Intron Retention in EIF2B5 as a Mechanism to Inhibit Translation. PLoS Biol. 2017 Sep 29;15(9):e2002623. doi: 10.1371/journal.pbio.2002623.
Wu X, Tudoran OM, Calin GA, Ivan M. The Many Faces of Long Noncoding RNAs in Cancer. Antioxid Redox Signal. 2017 Aug 10. doi: 10.1089/ars.2017.7293
Redis RS, Vela LE, Lu W, Ferreira de Oliveira J, Ivan C, Rodriguez-Aguayo C, Adamoski D, Pasculli B, Taguchi A, Chen Y, Fernandez AF, Valledor L, Van Roosbroeck K, Chang S, Shah M, Kinnebrew G, Han L, Atlasi Y, Cheung LH, Monroig P, Ramirez MS, Catela-Ivkovic T, Van L, Ling H, Gafa R, Kapitanovic S, Lanza G, Bankson JA, Huang P, Lai SY, Rosenblum MG, Radovich M, Ivan M, Bartholomeusz G, Liang H, Fraga M, Hanash S, Berindan-Neagoe I, Lopez-Berestein G, Ambrosio AL, Gomes Dias SM, Calin GA. Allele-specific reprograming of cancer metabolism by the long non-coding RNA, CCAT2. Mol Cell. 2016 Feb 3. pii:S1097-2765(16)00016-2. doi:10.1016/j.molcel.2016.01.015. PMID:26853146.
Mantel CR, O’Leary HA, Chitteti BR, Huang X, Cooper S, Hangoc G, Brustovetsky N, Srour EF, Lee MR, Messina-Graham S, Haas DM, Falah N, Kapur R, Pelus LM, Bardeesy N, Fitamant J, Ivan M, Kim K-S, Broxmeyer HE. Enhancing hematopoietic stem cell transplantation efficacy by mitigating oxygen shock. Cell 2015 Jun 9. pii: S0092-8674(15)00574-7. doi: 10.1016/j.cell.2015.04.054; PMID:26073944.
Fishel ML, Wu X, Devlin CM, Logsdon DP, Jiang Y, Luo M, He Y, Yu Z, Tong Y, Lipking KP, Maitra A, Rajeshkumar NV, Scandura G, Kelley MR, Ivan M. Apurinic/Apyrimidinic Endonuclease/ Redox Factor-1 (APE1/Ref-1) Redox Function Negatively Regulates NRF2. J Biol Chem. 2015 Jan 30; 290(5):3057-68. doi:10.1074/jbc.M114.621995 pii: jbc.M114.621995 PMID: 25492865.
Gee HE, Ivan C, Calin GA, Ivan M. Hypoxamirs and Cancer: from Biology to Targeted Therapy. Antioxid Redox Signal. 2014; Sep 10;21(8):1220-38. doi: 10.1089/ars.2013.5639. (corresponding author; featured article).
van den Beucken T, Koch E, Chu K, Rupaimoole R, Prickaerts P, Adriaens M, Voncken JW, Harris AL, Buffa F, Haider S, Starmans M, Yao C, Ivan M, Ivan C, Pecot C, Boutros P, Sood AK, Koritzinsky M, Wouters B. Hypoxia promotes stem cell phenotypes and poor prognosis through epigenetic regulation of DICER. Nature Communications 2014 5:5202 DOI: 10.1038/ncomms6203.
Ferdin J, Nishida N, Wu X, Nicoloso MS, Shah MY, Devlin C, Ling H, Shimizu M, Kumar K, Cortez MA, Ferracin M, Bi Y, Yang D, Czerniak B, Zhang W, Schmittgen TD, Voorhoeve MP, Reginato MJ, Negrini M, Davuluri RV, Kunej T, Ivan M, Calin GA. HINCUTs in Cancer: Hypoxia-Induced Non-Coding Ultraconserved Transcripts. Cell Death Differ, 2013 Dec;20(12):1675-87. doi: 10.1038/cdd.2013.119. PMID: 24037088; PMCID: PMC3824588.
Kumar K, Wigfield S, Gee HE, Devlin CM, Singleton D, Li JL, Buffa F, Huffman M, Sinn AL, Silver J, Turley H, Leek R, Harris AL, Ivan M. Dichloroacetate Reverses the Hypoxic Adaptation to Bevacizumab and Enhances its Antitumor Effects in Mouse Xenografts. J Mol Med, June 2013, 91(6): 749-758
