title: TH-302 in Combination with Radiotherapy Enhances the Therapeutic Outcome and Is Associated with Pretreatment [18F]HX4 Hypoxia PET Imaging.
abstract: OBJECTIVE
  Conventional anticancer treatments are often impaired by the presence of hypoxia. TH-302 selectively targets hypoxic tumor regions, where it is converted into a cytotoxic agent. This study assessed the efficacy of the combination treatment of TH-302 and radiotherapy in two preclinical tumor models. The effect of oxygen modification on the combination treatment was evaluated and the effect of TH-302 on the hypoxic fraction (HF) was monitored using [(18)F]HX4-PET imaging and pimonidazole IHC stainings.
  
  
  METHODS
  Rhabdomyosarcoma R1 and H460 NSCLC tumor-bearing animals were treated with TH-302 and radiotherapy (8 Gy, single dose). The tumor oxygenation status was altered by exposing animals to carbogen (95% oxygen) and nicotinamide, 21% or 7% oxygen breathing during the course of the treatment. Tumor growth and treatment toxicity were monitored until the tumor reached four times its start volume (T4×SV).
  
  
  RESULTS
  Both tumor models showed a growth delay after TH-302 treatment, which further increased when combined with radiotherapy (enhancement ratio rhabdomyosarcoma 1.23; H460 1.49). TH-302 decreases the HF in both models, consistent with its hypoxia-targeting mechanism of action. Treatment efficacy was dependent on tumor oxygenation; increasing the tumor oxygen status abolished the effect of TH-302, whereas enhancing the HF enlarged TH-302's therapeutic effect. An association was observed in rhabdomyosarcoma tumors between the pretreatment HF as measured by [(18)F]HX4-PET imaging and the T4×SV.
  
  
  CONCLUSIONS
  The combination of TH-302 and radiotherapy is promising and warrants clinical testing, preferably guided by the companion biomarker [(18)F]HX4 hypoxia PET imaging for patient selection.
authors: Department of Radiation Oncology (MaastRO), GROW-School for Oncology and Developmental Biology, Maastricht University Medical Centre, Maastricht, the Netherlands. sarah.peeters@maastrichtuniversity.nl.
authors: Sarah G J A
authors: SG
authors: Peeters
authors: Department of Radiation Oncology (MaastRO), GROW-School for Oncology and Developmental Biology, Maastricht University Medical Centre, Maastricht, the Netherlands.
authors: Catharina M L
authors: CM
authors: Zegers
authors: Department of Radiation Oncology (MaastRO), GROW-School for Oncology and Developmental Biology, Maastricht University Medical Centre, Maastricht, the Netherlands.
authors: Rianne
authors: R
authors: Biemans
authors: Department of Radiation Oncology (MaastRO), GROW-School for Oncology and Developmental Biology, Maastricht University Medical Centre, Maastricht, the Netherlands.
authors: Natasja G
authors: NG
authors: Lieuwes
authors: Department of Radiation Oncology (MaastRO), GROW-School for Oncology and Developmental Biology, Maastricht University Medical Centre, Maastricht, the Netherlands.
authors: Ruud G P M
authors: RG
authors: van Stiphout
authors: Department of Radiation Oncology (MaastRO), GROW-School for Oncology and Developmental Biology, Maastricht University Medical Centre, Maastricht, the Netherlands.
authors: Ala
authors: A
authors: Yaromina
authors: Threshold Pharmaceuticals, South San Francisco, California.
authors: Jessica D
authors: JD
authors: Sun
authors: Threshold Pharmaceuticals, South San Francisco, California.
authors: Charles P
authors: CP
authors: Hart
authors: Department of Radiology and Nuclear Medicine, VU University Medical Center, Amsterdam, the Netherlands.
authors: Albert D
authors: AD
authors: Windhorst
authors: Department of Radiation Oncology (MaastRO), GROW-School for Oncology and Developmental Biology, Maastricht University Medical Centre, Maastricht, the Netherlands.
authors: Wouter
authors: W
authors: van Elmpt
authors: Department of Radiation Oncology (MaastRO), GROW-School for Oncology and Developmental Biology, Maastricht University Medical Centre, Maastricht, the Netherlands.
authors: Ludwig J
authors: LJ
authors: Dubois
authors: Department of Radiation Oncology (MaastRO), GROW-School for Oncology and Developmental Biology, Maastricht University Medical Centre, Maastricht, the Netherlands.
authors: Philippe
authors: P
authors: Lambin
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D002289:Carcinoma, Non-Small-Cell Lung / Q000000981:diagnostic imaging / Q000628:therapy*; D015687:Cell Hypoxia; D059248:Chemoradiotherapy; D007093:Imidazoles; D008175:Lung Neoplasms / Q000000981:diagnostic imaging / Q000628:therapy*; D009593:Nitroimidazoles / Q000494:pharmacology* / Q000627:therapeutic use; D010752:Phosphoramide Mustards / Q000494:pharmacology* / Q000627:therapeutic use; D049268:Positron-Emission Tomography; D019275:Radiopharmaceuticals; D051381:Rats; D016896:Treatment Outcome; D014230:Triazoles; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; C562168:HX4 compound; D007093:Imidazoles; D009593:Nitroimidazoles; D010752:Phosphoramide Mustards; D019275:Radiopharmaceuticals; C552526:TH 302; D014230:Triazoles