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Ashkan  Emadi
 

Ashkan Emadi M.D., Ph.D.

Academic Title: Associate Professor
Primary Appointment: Medicine
Secondary Appointments: Pharmacology
aemadi@umm.edu
Location: UMMC, N9E24
Phone: (410) 328-2596
Fax: (410) 328-6896
 

Personal History:

Ashkan Emadi, M.D., Ph.D. joined the University of Maryland Marlene and Stewart Greenebaum Cancer Center (UMGCC) Leukemia and Hematologic Malignancies Program in May, 2012. He is Associate Professor of Medicine, Pharmacology and Experimental Therapeutics at the 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.

At UMGCC, Dr. Emadi serves as Director of the three-year Accreditation Council for Graduate Medical Education (ACGME)-accredited Hematology and Oncology Fellowship Program. He annually recruits and mentors five of the best candidates who are board eligible in internal medicine and wish to achieve training and certification in both hematology and medical oncology. As the program director, he is designated with authority and accountability for the operation of the fellowship program to fulfill all of the ACGME requirements. Dr. Emadi is the co-chair of the Clinical Research Committee (CRC) of UMGCC. In that role when the chair is unavailable, he conducts and chairs meetings, review protocols, and review resulting minutes. His prior experience at the US FDA is also called into service for questions that may arise around the need for investigational new drugs (INDs), and advise investigators in their interactions with the Agency to finalize that concern if it arises.

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, which exhibit HIV integrase inhibitory activity as well as anti-neoplastic activity. He was granted “Highest Standards of Academic Achievement Award” for his scholarly activity during PhD, and holds the patent on the compounds and their synthesis. He was awarded the prestigious “Martin and Mary Kilpatrick Award” for exceptional ability and promise in chemistry and outstanding achievement in chemical research.

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. Subsequently, Dr. Emadi was trained in Hematology and Medical Oncology Fellowship Program at Johns Hopkins University Sidney Kimmel Comprehensive Cancer Center. 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.


Research Interests and Relevant Publications:

1) Dr. Emadi’s early work focused on the discovery of novel methodologies for the regiospecific synthesis of conocurvone, a naturally occurring trimeric naphthoquinone with potent anti-HIV activity, and its derivatives. He and his colleagues reported the first examples of the use of hydroxyquinone anions in stepwise addition-elimination (substitution) reactions to form quinone-quinone bonds. The reactions lead to novel classes of halohydroxy- and halomethoxy dimeric naphthoquinones, which could be converted to trimeric naphthoquinone monomethyl ethers in just three simple steps, avoiding the use of organometallic reagents, which are traditionally used to make carbon-carbon bonds between sp2 carbons. The simplicity of the process, which utilizes inexpensive and readily available materials, will allow access to large quantities of both symmetrical and unsymmetrical dimeric and trimeric naphthoquinone derivatives.

Figure 1

Figure 1. Stepwise substitution leads to dimeric and trimeric naphthoquinones

  1. Emadi A, Harwood JS, Kohanim S, Stagliano KW. Regiocontrolled Synthesis of the Trimeric Quinone Framework of Conocurvone. Organic Letters. 2002; 4(4): 521-524.
  2. Stagliano KW, Lu Z, Emadi A, Harwood JS, Harwood CA. Effect of Methoxyl Group Position on the Regioselectivity of Ammonia Substitution Reactions Involving 3,3'-Dichloro-2,2'-binaphthoquinones. Journal of Organic Chemistry. 2004; 69(15): 5128-5131.
  3. Stagliano KW, Emadi A, Lu Z, Malinakova HC, Twenter B, Yu M, Holland LE, Rom AM, Harwood JS, Amin R, Johnson AA, Pommier Y. Regiocontrolled synthesis and HIV inhibitory activity of unsymmetrical binaphthoquinone and trimeric naphthoquinone derivatives of conocurvone. Bioorganic and Medicinal Chemistry. 2006; 14(16): 5651-5665.
  4. Stagliano KW, Emadi A. Anti-Retroviral Multi-Quinone Compounds and Regiospecific Synthesis Thereof. United States Patent and Trademark Office; Filed November 6, 2002; Application number: 10/288,685; U.S. Field of Search: 549/297,296,293 552/389,390,391 514/454,685; International Class: C07D 307/77; A61K 031/122; A61K 031/35; C07C 050/04. The United States Letters Patent Number 6,828,347 was issued on December 07, 2004. This invention was made with government support under NIH Grant #AI43687 awarded by the NIH.

2) Dr. Emadi is working on development of novel therapies that can simultaneously target different aspects of the cellular reduction-oxidation state in AML cells. A class of compounds that has shown great promise in targeting the cellular oxidative state is quinones, which are widely distributed in nature and all living cells. A particularly promising chemical class in the quinone family is the naphthoquinones with antibacterial, antifungal, antiviral, and antithrombotic derivatives. To this end, Dr. Emadi’s team subsequently determined structure-activity relationships (SARs) of 12 dimeric naphthoquinones analogs on the growth of 11 human AML, prostate and breast cancer cell lines, and found that these compounds selectively exert their anticancer activity via perturbation of cellular oxidative states. Through cyclic voltammetry studies, they have demonstrated that dimeric naphthoquinones can undergo four redox steps, of which the cathodic and anodic peak potentials can be tuned to specifically target cellular metabolic processes. For some of the naphthoquinones, cytotoxity could be predicted by redox potentials.

Figure 2

Figure 1. RedOx cycling (left), Cyclic voltammetry (right, up) and Lowest Unoccupied Molecular Orbital (LUMO) (right, down) of a dimeric naphthoquinone

  1. Emadi A, Ross AE, Cowan KM, Fortenberry YM, Vuica-Ross M. A Chemical Genetic Screen for Modulators of Asymmetrical 2,2´-Dimeric Naphthoquinone Cytotoxicity in Yeast. PLoS One. 2010; 5(5):e10846.
  2. Ricklis, RM, Vuica-Ross M, Brodsky RA, Sausville EA, Dang CV, Karp JE, Emadi A. Anti-leukemic activity of mitochondria-targeted asymmetrical 2-2'-binaphthoquinones. American Association for Cancer Research (AACR) Annual Meeting, Washington, DC; April 2010; Abstract 4539.
  3. Ross AE, Emadi A, Marchionni L, Hurley PJ, Simons BW, Schaeffer EM, Vuica-Ross M. Dimeric naphthoquinones represent a novel class of compounds with prostate cancer cytotoxicity. British Journal of Urology International. 2011; 108(3): 447-454.
  4. Emadi A, Le A, Harwood CA, Stagliano KW, Kamangar F, Ross AE, Cooper CR, Dang CV, Karp JE, Vuica-Ross M.  Metabolic and Electrochemical Mechanisms of Dimeric Naphthoquinones Cytotoxicity in Breast Cancer Cells. Bioorganic and Medicinal Chemistry. 2011; 19(23): 7057-7062.
  5. Emadi A, Sadowska M, Carter-Cooper B, Wonodi O, Muvarak N, Rassool F, Jaiswal A, Baer MR, Lapidus RG, Sausville EA. Dimeric Naphthoquinones: Novel Anti-Leukemic Agents Modulating Cellular Redox Status. American Society of Hematology (ASH) 55th Annual Meeting, New Orleans, LA; December 2013; Abstract 1290.
  6. Mukhi Pidugu LS, Mbimba JCE, Ahmad M, Pozharski E, Sausville EA, Emadi A, Toth EA. A Direct Interaction between NQO1 and a Chemotherapeutic Dimeric Napthoquinone. 2015. Under Review

3) It appears that cellular oxidative state is a credible target to selectively eradicate AML cells, as it is a fundamental property of each cell that is sufficiently different between leukemic and normal cells, yet its aberrancy shared among cytogenetically and mutationally different AML cells. To this end, in collaboration with Translational Laboratory Shared Services of UMGCC, we tested whether a short-time treatment of AML cells with sub-lethal dose of dichloroacetate (DCA), i.e. priming, followed by pharmacologic dose of arsenic trioxide (As2O3) in presence of low-dose DCA could produce insurmountable level of oxidative damage that kill AML cells. Using cellular cytotoxicity, apoptotic and metabolic assays with both established AML cell lines and primary AML cells, we found that priming with DCA significantly potentiated the cytotoxicity of As2O3 in AML cells in a synergistic manner. After obtaining FDA approval, one patient with AML whose disease was refractory to several lines of prior treatments was treated with this combination, and tolerated it well. Based on these results, an investigator initiated clinical trial of combination of oral DCA and intravenous As2O3 in patients with relapsed or refractory AML is underway.

Figure 3

  1. Emadi A, Gore SD. Arsenic trioxide - An old drug rediscovered. Blood Review. 2010; 24(4-5):191-199.
  2. Emadi A, Sadowska M, Carter-Cooper B, Bhatnagar V, van der Merwe I, Levis MJ, Sausville EA, Lapidus RG. Perturbation of cellular oxidative state induced by dichloroacetate and arsenic trioxide for treatment of acute myeloid leukemia. Leukemia Research. 2015; 39(7):719-729.

4) 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.  Clinical and translational research has focused on treatment of patients with AML with isocitrate dehydrogenase 1 and 2 (IDH1 & IDH2) mutations. IDH1/2 catalyze the conversion of isocitrate to a-ketoglutarate with the production of NADPH. Mutants of IDH1 and IDH2 found in glioma, glioblastoma, cartilaginous tumor, cholangiocarcinoma of intrahepatic origin, and acute myeloid leukemia converts a-ketoglutarate (2-oxoglutarate) to 2-hydroxyglutarate (a potential tumor biomarker) with the consumption of NADPH. The primary source for a-ketoglutarate under this condition is shown to be extracellular glutamine.

The discovery of IDH1/2 mutations and their impact on important proteomic, epigenetic and metabolic pathways in cancer cells has triggered intensive efforts to develop novel and targeted therapies. IDH1/2 inhibitors are currently under early phase clinical investigation, with promising suggestion of efficacy. Other therapeutic approaches under preclinical and clinical investigation in this population include DNA methyltransferase inhibitors and agents that target glutamine metabolism through inhibition of glutaminase or depletion of serum glutamine by asparaginase products.

Figure 4

  1. Emadi A. At the Crossroads: Tumor Metabolism and Epigenetics. Science Translational Medicine. 2011; 3 (82): 82ec68.
  2. Emadi A. A Curious Case of Cellular Metabolism. Science Translational Medicine. 2011; 3 (90): 90ec103.
  3. Emadi A. Cancer’s Food Network. Science Translational Medicine. 2011; 3 (98): 98ec139.
  4. Emadi A. Bidirectional Dance of Glutamine. Science Translational Medicine. 2012; 4 (118): 118ec12.
  5. Fathi AT, Sadrzadeh H, Foster J, Burke M, Borger DR, Lopez H, Iafrate AJ, Ballen KK, Amrein PC, Attar EC, Straley K, Yen K, Schenkein DP, Emadi A, Neuberg DS, Stone RM, Chen YB. Prospective serial evaluation of 2-hydroxyglutarate, during treatment of newly diagnosed acute myeloid leukemia, to assess disease activity and therapeutic response. Blood, 2012; 29; 120(23):4649-52.
  6. Riggins GJ, Seltzer MJ, Tsukamoto T, Dang CV, Emadi A. Metabolic Inhibitor Against Tumors Having an IDH Mutation. U.S. Provisional Patent Application Nos. 61/333,010, filed May 10, 2010; 61/357,674, filed June 23, 2010; and 61/383,426, filed September 16, 2010. International Patent Classification: A61K 31/433 (2006.01) and A61P 35/00 (2006.01); International Application Number: PCT/US2011/035841; International Filing Date: May 10, 2011; International Patent Publication Number: WO 2011/143160 A2.
  7. Emadi A, Jun SA, Tsukamoto T, Fathi AT, Minden MD, Dang CV. Inhibition of Glutaminase Selectively Suppresses the Growth of Primary AML Cells with IDH Mutations. Experimental Hematology. 2014; 42(4): 247-251.
  8. Emadi A, Zokaee H, Sausville EA. Asparaginase in the Treatment of Non-ALL Hematologic Malignancies. Cancer Chemotherapy and Pharmacology. 2014; 73(5):875-883.
  9. Emadi A, Faramand R, Carter-Cooper B, Tolu S, Ford LA, Lapidus RG, Wetzler M, Wang ES, Etemadi A, Griffiths EA. Presence of isocitrate dehydrogenase mutations may predict clinical response to hypomethylating agents in patients with acute myeloid leukemia. American Journal of Hematology. 2015; 90(5):E77-79.
  10. Fathi AT, Wander SA, Faramand R, Emadi A. Biochemical, epigenetic, and metabolic approaches to target IDH mutations in acute myeloid leukemia. Seminars in Hematology. 2015; 52(3):165-171.

Clinical Specialty:

Acute Myeloid Leukemia
Acute Lymphoblastic Leukemia
Myelodysplastic Syndromes
Myeloproliferative Neoplasms
Cytopenia


Publications:

Other Selected Publications

  1. Segal JB, Brotman DJ, Necochea AJ, Emadi A, Samal L, Wilson LM, Crim MT, Bass EB. The Predictive Value of Factor V Leiden and Prothrombin G20210A in Adults with Venous Thromboembolism and in Family Members of Those with a Mutation: A Systematic Review of the Literature. JAMA. 2009; 301(23): 2472-2485.
  2. Emadi A, Brodsky RA. Successful discontinuation of anticoagulation following eculizumab administration in paroxysmal nocturnal hemoglobinuria. American Journal of Hematology. 2009; 84(10): 699-701.
  3. Emadi A, Jones RJ, Brodsky RA. Cyclophosphamide and Cancer: Golden Anniversary. Nature Reviews Clinical Oncology. 2009; 6(11): 638-647.
  4. Emadi A, Crim MT, Brotman DJ, Necochea AJ, Samal L, Wilson LM, Bass EB, Segal JB. Analytic Validity of Genetic Tests to Identify Factor V Leiden and Prothrombin G20210A. American Journal of Hematology. 2010; 85(4): 264-270.
  5. Antonarakis ES, Emadi A. Ruthenium-based Chemotherapeutics: Are they ready for prime time? Cancer Chemotherapy and Pharmacology. 2010; 66(1): 1-9.
  6. Emadi A, Karp JE. The Clinically Relevant Pharmacogenomic Changes in Acute Myelogenous Leukemia. Pharmacogenomics. 2012; 13(11):1257-1269.
  7. Boffetta P, Islami F, Vedanthan R, Pourshams A, Kamangar F, Khademi H, Etemadi A, Salahi R, Semnani S, Emadi A, Abnet CC, Brennan P, Pharoah PD, Dawsey SM, Malekzadeh R. A U-shaped relationship between haematocrit and mortality in a large prospective cohort study. International Journal of Epidemiology, 2013; 42(2):601-615.
  8. Bhatnagar B, Duong VH, Gourdin TS, Tidwell ML, Chen Q, Ning Y, Emadi A, Sausville EA, Baer MR. Ten-day decitabine as initial therapy for newly diagnosed acute myeloid leukemia patients unfit for intensive chemotherapy. Leukemia & Lymphoma. 2014; 55(7):1533-1537.
  9. Sammons SL, Pratz KW, Smith BD, Karp JE, Emadi A. Sorafenib is tolerable and improves clinical outcomes in patients with FLT3-ITD acute myeloid leukemia prior to stem cell transplant, and after relapse post-transplant. American Journal of Hematology. 2014; 89(9):936-938.
  10. Oliver N, Short B, Thein M, Duong VH, Tidwell ML, Sausville EA, Baer MR, Kamangar F, Emadi A. Treatment of Catheter-related Deep Vein Thrombosis in Acute Leukemia Patients with Anticoagulation. Leukemia & Lymphoma. 2015; 56(7):2082-2086.
  11. Etemadi A, Kamangar F, Islami F, Poustchi H, Pourshams A, Brennan P, Boffetta P, Malekzadeh R, Dawsey SM, Abnet CC, Emadi A. Mortality and cancer in relation to ABO blood group phenotypes in the Golestan Cohort Study. BMC Medicine. 2015;13(1):8.