Ashkan Emadi, MD, PhD

Research Interests

Dr. Emadi is a devoted basic/translational researcher.

In his lab (https://emadicancerlab.com), Dr. Emadi directs cutting-edge preclinical research focused on exploiting the amino acid metabolism of hematologic and epithelial and mesenchymal cancer cells. His group is one of the world leaders on targeting glutamine metabolism and dependency in acute myeloid leukemia (AML), pancreatic adenocarcinoma, mesothelioma, brain tumors including both isocitrate dehydrogenase (IDH) mutant astrocytoma and IDH wild type glioblastoma.

Dr. Emadi has had several grants and patents on asparaginase combination therapy for blood cancers and solid tumors investigating mechanistically driven synergism between glutamine depletion and other chemotherapeutics as well as the effect on global mRNA translation in cancer cells. He has designed and conducted several novel state-of-the-arts clinical trials (NCT02283190, NCT04666649, NCT04953780, NCT02835729, NCT04827745). Dr. Emadi was the first to report that in patients with AML, plasma glutamine can safely be depleted to an undetectable level with promising antileukemic effect.

As a recent example of his work, Dr. Emadi and his team translated their preclinical discovery of venetoclax (Ven) and pegcrisantaspase (PegC) as a novel, well-tolerated and highly active regimen in vivo for the treatment of AML with complex karyotypes into an investigator-initiated clinical trial (NCT04666649). The mechanism of action of VenPegC combination is completely unique to the field that could overcome Ven resistance in AML by inhibition of cap-dependent mRNA translation through increasing the inhibitory interaction between 4EBP1 and its substrate eIF4E resulting in decreased expression of protein involved in Ven-resistance such as Mcl1. VenPegC is tolerable at maximum tolerated dose and did not cause venous thromboembolism, hemorrhage, hepatic failure, pancreatitis, or hypersensitivity reactions. VenPegC induced approximately 35% complete remission in heavily pretreated AML patients even with prior exposure to Ven; majority of these patients had limited or no therapeutic options. This treatment is entirely feasible to deliver in outpatient setting and oncologists treating patients with leukemia are quite familiar with their administration, with their therapeutic potential and their potential toxicities.

Grants and Research

See attached CV

Publications

Contributions to Science

1. Discovery of novel methodologies for the regiospecific synthesis of oligomeric naphthoquinones. Dr. Emadi was the first to use hydroxyquinone anions in the stepwise substitution reactions to form quinone-quinone bonds. This process utilizes inexpensive and readily available materials to synthesize large scale dimeric and trimeric naphthoquinones. This synthetic route forms a chemical bond between two SP² carbons in quinone systems through a stepwise replacement of the halogens in 2,3-dihalonaphthoquinones by hydroxyquinone as an active methylene. This method has been successfully used and multiply cited by organic and medicinal chemists worldwide to synthesize medicinal oligomeric quinones.
   a. Emadi A, Harwood JS, Kohanim S, Stagliano KW. Regiocontrolled synthesis of the trimeric quinone framework of conocurvone. Org Lett. 2002 Feb 21;4(4):521–4.
   b. Stagliano KW, Emadi A, Lu Z, Malinakova HC, Twenter B, et al. Regiocontrolled synthesis and HIV inhibitory activity of unsymmetrical binaphthoquinone and trimeric naphthoquinone derivatives of conocurvone. Bioorg Med Chem. 2006 Aug 15;14(16):5651–65.
   c. Stagliano KW, Emadi A. Anti-retroviral multi-quinone compounds and regiospecific synthesis thereof. United States patent 6,828,347. 2004 Dec 7.
   d. 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 May 26;5(5):e10846. PubMed PMID: 20520766.

2. Antineoplastic activity of dimeric naphthoquinone. Dr. Emadi and his colleagues discovered that halogenated, aziridinyl, and hydroxyethyl amine dimeric naphthoquinones (BiQs) are active against malignant cells including acute myeloid leukemia (AML), breast cancer, and prostate cancers with remarkable potency and selectivity. BiQs exert their anticancer activities through targeting mitochondrial respiration and cellular redox states, alkylating DNA, and inhibiting NQO1.
   a. Emadi A, Le A, Harwood CA, Stagliano KW, Kamangar F, et al. Metabolic and electrochemical mechanisms of dimeric naphthoquinones cytotoxicity in breast cancer cells. Bioorg Med Chem. 2011 Dec 1;19(23):7057–7062.
   b. Lapidus RG, Carter-Cooper BA, Sadowska M, Choi EY, Wonodi O, Muvarak N, Natarajan K, Mukhi Pidugu LS, Jaiswal AK, Toth EA, Rassool FV, Etemadi A, Sausville EA, Baer MR, Emadi A. Hydroxylated dimeric naphthoquinones increase generation of reactive oxygen species, induce apoptosis of AML cells and are not substrates of the multidrug resistance proteins. Pharmaceuticals (Basel). 2016 Jan 19;9(1).
   c. Carter-Cooper BA, Fletcher S, Ferraris D, Choi EY, Kronfli D, Dash S, Truong P, Sausville EA, Lapidus RG, Emadi A. Synthesis, characterization and antineoplastic activity of bis-aziridinyl dimeric naphthoquinone - A novel class of compounds with potent activity against acute myeloid leukemia cells. Bioorg Med Chem Lett. 2017 Jan; 27(1):6–10.
   d. Ferraris D, Lapidus R, Truong P, Bollino D, Carter-Cooper B, Lee M, Chang E, LaRossa-Garcia M, Dash S, Gartenhaus R, Choi EY, Kipe O, Lam V, Mason K, Palmer R, Williams E, Ambulos N, Kamangar F, Zhang Y, Kapadia B, Jing Y, Emadi A. Pre-Clinical Activity of Amino-Alcohol Dimeric Naphthoquinones as Potential Therapeutics for Acute Myeloid Leukemia. Anticancer Agents Med Chem. 2022;22(2):239-253. 

3. Exploiting glutamine metabolic pathways for cancer treatment. Dr. has used the glutaminase activity of clinical asparaginases (both E. coli and Erwinia chrysanthemi [Crisantaspase]) to effectively deplete glutamine and investigate its effect on and eIF4E-4EBP1 interaction on cap binding complex and inhibition of cap-dependent translation. For the first time, Dr. Emadi and his team reported that crisantaspase resulted in complete plasma glutamine depletion in patients and was associated with antileukemic activity in relapsed/refractory AML with no dose-limiting toxicity.
   a. Emadi A, Law JY, Strovel ET, Lapidus RG, Jeng LJB, et al. Asparaginase Erwinia Chrysanthemi effectively depletes plasma glutamine in adult patients with relapsed or refractory acute myeloid leukemia. Cancer Chemother Pharmacol. 2018 Jan;81(1):217-222.
   b. Emadi A, Kapadia B, Bollino D, Bhandary B, Baer MR, Niyongere S, Strovel ET, Kaizer H, Chang E, Choi EY, Ma X, Tighe KM, Carter-Cooper B, Moses BS, Civin CI, Mahurkar A, Shetty AC, Gartenhaus RB, Kamangar F, Lapidus RG. Venetoclax and pegcrisantaspase for complex karyotype acute myeloid leukemia. Leukemia. 2021 Jul;35(7):1907-1924.
   c. Kapadia B, Shetty AC, Bollino D, Bhandary B, Lapidus RG, Mahmood K, Mahurkar A, Gartenhaus RB, Eckert RL, Emadi A. Translatome changes in acute myeloid leukemia cells post-exposure to pegcrisantaspase and venetoclax. Exp Hematol. 2022 Apr;108:55-63.
   d. Emadi A, Lapidus RG. Asparaginase-induced Glutamine Depletion Combined with BCL-2 Inhibition for Treatment of Hematologic and Solid Cancers. UMB Docket No: AE-2019-063; PCT No. PCT/US2019/067374, PCT Filed 12/19/2019; USPTO Application No. 17/415,344, Filing Date 06/17/2021. Publication No. US-2022-0054606-A1, Publication Date 02/24/2022.

4. Investigator-initiated clinical trials targeting amino acid metabolisms for treatment of acute myeloid and lymphoblastic leukemias (AML & ALL).
   a. An Open-Label, Single-Arm Pharmacokinetic Study of Intravenous Erwinaze (asparaginase Erwinia chrysanthemi) for the Treatment of Adult Patients with Acute Myeloid Leukemia (AML) with or without Isocitrate Dehydrogenase (IDH) Mutations (GCCC1336, IND 121263), NCT02283190.
   b. Phase 1b / Randomized Phase 2a Trial of Indoximod in Combination with Idarubicin and Cytarabine in Patients with Newly Diagnosed AML (GCCC1562, IND 127155), NCT02835729.
   c. Pegcrisantaspase in Combination with Venetoclax for Treatment of Relapsed or Refractory Acute Myeloid Leukemia (GCCC2087, IND 154601), NCT04666649.
   d. A Phase 1 Trial of Calaspargase Pegol-mknl in Combination with High Dose Cytarabine and Idarubicin in Adult Patients with Newly Diagnosed Acute Myeloid Leukemia (GCCC2157, IND 157111), NCT04953780.