Ashkan Emadi, M.D., Ph.D. joined the University of Maryland Marlene and Stewart Greenebaum Cancer Center Leukemia and Hematologic Malignancies Program in May, 2012, and is Associate Professor of Medicine, University of Maryland School of Medicine. He previously served as Medical Officer at the Division of Hematology Products (DHP), Office of Hematology and Oncology Products (OHOP), Center for Drug Evaluation and Research (CDER), United States Food and Drug Administration (FDA), and as Visiting Scientist at Division of Adult Hematology, Department of Internal Medicine, School of Medicine, Johns Hopkins University.
Dr. Emadi received his medical doctorate (M.D.) at Tehran University of Medical Sciences in 1996 and his Ph.D. in Organic Chemistry at the Illinois Institute of Technology in 2004. He developed novel methodologies for the regiospecific synthesis of multiple naphthoquinone derivatives related to the natural product conocurvone and exhibiting HIV integrase inhibitory activity. He was granted “Highest Standards of Academic Achievement Award” for this work, and holds the patent on the compounds and their synthesis. Following completion of his Ph.D., he completed his internship and residency in Internal Medicine at the University of Kentucky and the University of Cincinnati, respectively. During his Hematology/Oncology fellowship at Johns Hopkins University Sidney Kimmel Comprehensive Cancer Center, Dr. Emadi explored different metabolic pathways of cancer cells to develop targeted chemotherapeutic agents for the treatment of leukemia and other hematologic malignancies.
Dr. Emadi's translational and clinical research is focused on exploiting and targeting cancer metabolism. He works on developing new drugs and novel targets for the treatment of acute leukemias and other blood cancers. Dr. Emadi has experience and in-depth understanding of the multiple aspects of cancer drug development including basic organic chemistry and molecular synthesis, in vitro and in vivo studies, and all phases of clinical trials as well as regulatory science.
In previous work, we have investigated the therapeutic targeting of mitochondria as a potential anti-leukemia strategy. We studied novel dimeric naphthoquinones as potential antitumor agents for both epithelial and hematologic malignancies. After a comprehensive mechanistic study by performing a chemical genetic screen in yeast, we demonstrated that dimeric naphthoquinones possess selective cytotoxic effects on androgen-independent and androgen-responsive prostate cancer cell lines, breast cancer cell lines with different metabolic signatures, and various leukemia cell lines. Significant increase in reactive oxygen species, decrease in oxygen consumption and ATP production, induced by dimeric naphthoquinone, suggest that oxidative stress and mitochondrial dysfunction are mechanisms by which these agents exert their cytotoxic effects. We are currently investigating generation of apoptosis, mitochondrial membrane depolarization, and caspase activation induced by dimeric naphthoquinones in leukemia cell lines that are resistant to chemotherapies. Through our collaboration with other groups, we are also studying the effects of different dimeric naphthoquinone analogues on mitogen-activated protein kinase (MAPK) and on extracellular signal-regulated protein kinases (ERK1/2), as well as on anti-apoptotic regulatory proteins, such as Mcl-1, and on pro-apoptotic proteins, such as BAX in acute myeloid leukemia cell lines.
Many tumors, including lymphomas and leukemias, display distinct metabolic alterations as enhanced uptake of glucose and glutamine, which is exploited for the detection of many cancers through PET scan. The understanding of molecular and oncogenic mechanisms behind how cancer cells reprogram their metabolism to compensate for increased energy demand and enhanced anabolism, cell proliferation and tissue invasion is beginning to emerge and their therapeutic implication is being explored. We have explored targeting various glycolytic enzymes controlled by MYC and the hypoxia-inducible factor 1 (HIF-1) in different leukemia and lymphoma models.
Our recent work has focused on targeting glutamine metabolism in acute myelogenous leukemia cells with isocitrate dehydrogenase gene (IDH-1 and IDH-2) mutations. Isocitrate dehydrogenases, IDH1 and IDH2, catalyze the conversion of isocitrate to α-ketoglutarate with the production of NADPH (reaction shown below in top line). Mutants of IDH1 and IDH2 found in glioma, glioblastoma, cartilaginous tumor, cholangiocarcinoma of intrahepatic origin, and acute myelogenous leukemia converts α-ketoglutarate (2-oxoglutarate) to 2-hydroxyglutarate (a potential tumor biomarker) with the consumption of NADPH (reaction shown below on bottom line). The primary source for α-ketoglutarate under this condition is shown to be extracellular glutamine. We are exploring different pathways and methods to target leukemic cells with this distinct metabolic feature.
Recently, it has been demonstrated that IDH1/2 mutations associate with specific cytosine methylation, and aberrant DNA hypermethylation is the dominant feature of IDH1/2-mutant AMLs. Based on recent findings, the scheme below demonstrates the chemical reactions involve in DNA cytosine demethylation. 2HG (produced by IDH1/2-mutant AMLs) is a competitive inhibitor of multiple αKG-dependent histone demethylases, prolyl hydroxylases, and TET hydroxylases.
Expression of IDH1/2 mutants and loss of TET2 increase expression of stem cell markers and impaired myeloid differentiation. These data indicate that IDH mutation is at the crossroads of tumor metabolism and epigenetics. In the laboratory and in the clinic, we are working to discover novel therapeutic strategies for treatment of patients with this unique form of AML.