TY - JOUR
T1 - TH-302 in Combination with Radiotherapy Enhances the Therapeutic Outcome and Is Associated with Pretreatment [F-18]HX4 Hypoxia PET Imaging
AU - Peeters, Sarah G. J. A.
AU - Zegers, Catharina M. L.
AU - Biemans, Rianne
AU - Lieuwes, Natasja G.
AU - van Stiphout, Ruud G. P. M.
AU - Yaromina, Ala
AU - Sun, Jessica D.
AU - Hart, Charles P.
AU - Windhorst, Albert D.
AU - van Elmpt, Wouter
AU - Dubois, Ludwig J.
AU - Lambin, Philippe
PY - 2015/7/1
Y1 - 2015/7/1
N2 - Purpose: 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 [F-18]HX4-PET imaging and pimonidazole IHC stainings. Experimental Design: 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 x 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 [F-18]HX4-PET imaging and the T4 x SV. Conclusions: The combination of TH-302 and radiotherapy is promising and warrants clinical testing, preferably guided by the companion biomarker [F-18]HX4 hypoxia PET imaging for patient selection.
AB - Purpose: 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 [F-18]HX4-PET imaging and pimonidazole IHC stainings. Experimental Design: 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 x 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 [F-18]HX4-PET imaging and the T4 x SV. Conclusions: The combination of TH-302 and radiotherapy is promising and warrants clinical testing, preferably guided by the companion biomarker [F-18]HX4 hypoxia PET imaging for patient selection.
U2 - 10.1158/1078-0432.CCR-15-0018
DO - 10.1158/1078-0432.CCR-15-0018
M3 - Article
C2 - 25805800
SN - 1078-0432
VL - 21
SP - 2984
EP - 2992
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 13
ER -