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. Stepwise substitution leads to dimeric and trimeric naphthoquinones
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 1. RedOx cycling (left), Cyclic voltammetry (right, up) and Lowest Unoccupied Molecular Orbital (LUMO) (right, down) of a dimeric naphthoquinone
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.
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.
Acute Myeloid Leukemia