title: Hypoxia-Activated Prodrug TH-302 Targets Hypoxic Bone Marrow Niches in Preclinical Leukemia Models.
abstract: OBJECTIVE
  To characterize the prevalence of hypoxia in the leukemic bone marrow, its association with metabolic and transcriptional changes in the leukemic blasts and the utility of hypoxia-activated prodrug TH-302 in leukemia models.
  
  
  METHODS
  Hyperpolarized magnetic resonance spectroscopy was utilized to interrogate the pyruvate metabolism of the bone marrow in the murine acute myeloid leukemia (AML) model. Nanostring technology was used to evaluate a gene set defining a hypoxia signature in leukemic blasts and normal donors. The efficacy of the hypoxia-activated prodrug TH-302 was examined in the in vitro and in vivo leukemia models.
  
  
  RESULTS
  Metabolic imaging has demonstrated increased glycolysis in the femur of leukemic mice compared with healthy control mice, suggesting metabolic reprogramming of hypoxic bone marrow niches. Primary leukemic blasts in samples from AML patients overexpressed genes defining a "hypoxia index" compared with samples from normal donors. TH-302 depleted hypoxic cells, prolonged survival of xenograft leukemia models, and reduced the leukemia stem cell pool in vivo In the aggressive FLT3/ITD MOLM-13 model, combination of TH-302 with tyrosine kinase inhibitor sorafenib had greater antileukemia effects than either drug alone. Importantly, residual leukemic bone marrow cells in a syngeneic AML model remain hypoxic after chemotherapy. In turn, administration of TH-302 following chemotherapy treatment to mice with residual disease prolonged survival, suggesting that this approach may be suitable for eliminating chemotherapy-resistant leukemia cells.
  
  
  CONCLUSIONS
  These findings implicate a pathogenic role of hypoxia in leukemia maintenance and chemoresistance and demonstrate the feasibility of targeting hypoxic cells by hypoxia cytotoxins.
authors.affiliation: Department of Leukemia, University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Juliana
authors.initials: J
authors.lastname: Benito
authors.affiliation: Imaging Physics, University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Marc S
authors.initials: MS
authors.lastname: Ramirez
authors.affiliation: Department of Experimental Diagnostic Imaging, University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Niki Zacharias
authors.initials: NZ
authors.lastname: Millward
authors.affiliation: Department of Leukemia, University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Juliana
authors.initials: J
authors.lastname: Velez
authors.affiliation: Department of Leukemia, University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Karine G
authors.initials: KG
authors.lastname: Harutyunyan
authors.affiliation: Department of Leukemia, University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Hongbo
authors.initials: H
authors.lastname: Lu
authors.affiliation: Department of Leukemia, University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Yue-Xi
authors.initials: YX
authors.lastname: Shi
authors.affiliation: Department of Leukemia, University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Polina
authors.initials: P
authors.lastname: Matre
authors.affiliation: Department of Leukemia, University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Rodrigo
authors.initials: R
authors.lastname: Jacamo
authors.affiliation: Department of Leukemia, University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Helen
authors.initials: H
authors.lastname: Ma
authors.affiliation: Department of Hematopathology, University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Sergej
authors.initials: S
authors.lastname: Konoplev
authors.affiliation: Department of Leukemia, University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Teresa
authors.initials: T
authors.lastname: McQueen
authors.affiliation: Department of Bioinformatics and Computational Biology, University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Andrei
authors.initials: A
authors.lastname: Volgin
authors.affiliation: Institute for Applied Cancer Science, University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Marina
authors.initials: M
authors.lastname: Protopopova
authors.affiliation: Department of Leukemia, University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Hong
authors.initials: H
authors.lastname: Mu
authors.affiliation: Imaging Physics, University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Jaehyuk
authors.initials: J
authors.lastname: Lee
authors.affiliation: Cancer Systems Imaging, University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Pratip K
authors.initials: PK
authors.lastname: Bhattacharya
authors.affiliation: Institute for Applied Cancer Science, University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Joseph R
authors.initials: JR
authors.lastname: Marszalek
authors.affiliation: Department of Lymphoma and Myeloma, University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: R Eric
authors.initials: RE
authors.lastname: Davis
authors.affiliation: Imaging Physics, University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: James A
authors.initials: JA
authors.lastname: Bankson
authors.affiliation: Department of Leukemia, University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Jorge E
authors.initials: JE
authors.lastname: Cortes
authors.affiliation: Threshold Pharmaceuticals, Inc., South San Francisco, California.
authors.forename: Charles P
authors.initials: CP
authors.lastname: Hart
authors.affiliation: Department of Leukemia, University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Michael
authors.initials: M
authors.lastname: Andreeff
authors.affiliation: Department of Leukemia, University of Texas MD Anderson Cancer Center, Houston, Texas. mkonople@mdanderson.org.
authors.forename: Marina
authors.initials: M
authors.lastname: Konopleva
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001853:Bone Marrow / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D020869:Gene Expression Profiling; D015973:Gene Expression Regulation, Leukemic; D006801:Humans; D000860:Hypoxia / Q000378:metabolism*; D007938:Leukemia / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D008279:Magnetic Resonance Imaging; D051379:Mice; D009593:Nitroimidazoles / Q000494:pharmacology*; D010752:Phosphoramide Mustards / Q000494:pharmacology*; D011355:Prodrugs / Q000494:pharmacology*; D016896:Treatment Outcome; D059016:Tumor Microenvironment / Q000187:drug effects*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D009593:Nitroimidazoles; D010752:Phosphoramide Mustards; D011355:Prodrugs; C552526:TH 302