TH-302 in Combination with Radiotherapy Enhances the Therapeutic Outcome and Is Associated with Pretreatment [18F]HX4 Hypoxia PET Imaging

Abstract

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 [ 18 F]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 (T4ÂSV).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 0 s therapeutic effect. An association was observed in rhabdomyosarcoma tumors between the pretreatment HF as measured by [ 18 F]HX4-PET imaging and the T4ÂSV.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.

Preclinical Assessment of Efficacy of Radiation Dose Painting Based on Intratumoral FDG-PET Uptake

“…This preclinical investigation, however, cannot be directly compared with this study because uniform irradiation was delivered to the tumors stratified by median SUV max to low or high FDG uptake tumors assuming that each tumor represents a subvolume of a tumor in a single patient, whereas in this study, the nonuniform dose distributions were applied on the basis of intratumoral FDG uptake. Here, we used lower radiation doses of 8 and 12 Gy that have been shown previously to induce significant growth delay in rhabdomyosarcoma tumor model when delivered uniformly (33,35). Moreover, TGT V2 increases with increasing uniform radiation doses ( Supplementary Fig.…”

“…250 g) and previously well-characterized syngeneic rhabdomyosarcoma R1 tumor model (kindly provided by W. Landuyt, Experimental Radiotherapy, Katholieke Universiteit, Leuven, Belgium; refs. [29][30][31][32][33]. For the experiments, tumor pieces (ca.…”

“…Several hours after PET/CT imaging, the tumors were either left untreated or a mean single dose to the GTV of 8 or 12 Gy was delivered as uniform or heterogeneous irradiation. The two dose levels applied in this study have been selected on the basis of the previous results, demonstrating significant growth delay after uniform irradiation with these doses (33,35). In all dose groups with heterogeneous irradiation, the BTV was defined to represent 30% of the GTV.…”

Clinical development of new drug–radiotherapy combinations

“…Earlier consideration of potential radiotherapy-related biomarkers or biomarkers associ ated with mechanisms underpinning a synergistic drug-radiotherapy combination might help reduce the risk of failure in the phase III setting. 'Window of opportunity' clinical trials permit the development of tissue and imaging biomarkers in a short period of time before surgery or other definitive treatment 73,74 . As gains in the therapeutic index can be achieved by improving efficacy or reducing toxicity, phase II designs that support co-primary end points could be useful 75 .…”

The promise of multiparametric imaging in oncology: how do we move forward?

“…Multiparametric imaging might facilitate this approach by enabling the selection of the appropriate molecular imaging tools that quantify tumour properties or stratify patients. A recent example from the preclinical arena for precision medicine is hypoxia-activated prodrugs that only show efficacy in hypoxic tumours [30]. Molecular imaging using hypoxia PET tracers could allow identification of those patients who would benefit from these drugs.…”