Combined endogenous MR biomarkers to assess changes in tumor oxygenation induced by an allosteric effector of hemoglobin

Abstract

Hypoxia is a crucial factor in cancer therapy, determining prognosis and the effectiveness of treatment. Although efforts are being made to develop methods for assessing tumor hypoxia, no markers of hypoxia are currently used in routine clinical practice. Recently, we showed that the combined endogenous MR biomarkers, R1 and R2*, which are sensitive to [dissolved O2] and [dHb], respectively, were able to detect changes in tumor oxygenation induced by a hyperoxic breathing challenge. In this study, we further validated the ability of the combined MR biomarkers to assess the change in tumor oxygenation induced by an allosteric effector of hemoglobin, myo‐inositol trispyrophosphate (ITPP), on rat tumor models. ITPP induced an increase in tumor pO2, as observed using L‐band electron paramagnetic resonance oximetry, as well as an increase in both R1 and R2* MR parameters. The increase in R1 indicated an increase in [O2], whereas the increase in R2* resulted from an increase in O2 release from blood, inducing an increase in [dHb]. The impact of ITPP was then evaluated on factors that can influence tumor oxygenation, including tumor perfusion, saturation rate of hemoglobin, blood pH and oxygen consumption rate (OCR). ITPP decreased blood [HbO2] and significantly increased blood acidity, which is also a factor that right‐shifts the oxygen dissociation curve. No change in tumor perfusion was observed after ITPP treatment. Interestingly, ITPP decreased OCR in both tumor cell lines. In conclusion, ITPP increased tumor pO2 via a combined mechanism involving a decrease in OCR and an allosteric effect on hemoglobin that was further enhanced by a decrease in blood pH. MR biomarkers could assess the change in tumor oxygenation induced by ITPP. At the intra‐tumoral level, a majority of tumor voxels were responsive to ITPP treatment in both of the models studied.

The Role of Imaging Biomarkers to Guide Pharmacological Interventions Targeting Tumor Hypoxia

“…Attempts were also made to correlate R 2 * values with expression of HIF-1α: the mean R 2 * value correlated moderately with the level of HIF-1α in breast invasive ductal carcinoma (Liu et al, 2013), in human glioma (Tóth et al, 2013), but no correlation was found in renal carcinoma (Li et al, 2015). Using pharmacological manipulation of tumor oxygenation, it was found that the evolution of R 2 * was consistent with changes in tumor oxygenation after isosorbide dinitrate administration (Jordan et al, 2000) and the hemoglobin modifier ITTP (Cao-Pham et al, 2020). For the latter, the increase in R 2 * resulted from an increase in oxygen release from blood, inducing an increase in [dHb] (Cao-Pham et al, 2020).…”

“…Using pharmacological manipulation of tumor oxygenation, it was found that the evolution of R 2 * was consistent with changes in tumor oxygenation after isosorbide dinitrate administration (Jordan et al, 2000) and the hemoglobin modifier ITTP (Cao-Pham et al, 2020). For the latter, the increase in R 2 * resulted from an increase in oxygen release from blood, inducing an increase in [dHb] (Cao-Pham et al, 2020). However, the evolution of R 2 * was not predictive of evolution of tumor oxygenation (as measured by EPR oximetry) after administration of inhibitors of oxygen consumption (insulin and AINS) (Jordan et al, 2006b) or after the RSR13 hemolobin modifier (Hou et al, 2004).…”

“…Another strategy to increase the oxygen delivery without altering the perfusion is to promote the release of oxygen by hemoglobin (Hb). It has been shown that allosteric effectors (such as efaproxiral or myo-inositol trispyrophosphate) binding to Hb results in a decreased hemoglobin-oxygen (Hb-O 2 ) affinity and an increased tumor oxygenation (Teicher et al, 1998;Khandelwal et al, 1999;Amorino et al, 2001;Hou et al, 2004;Hou et al, 2005;Suh et al, 2006;Hou et al, 2007;Scott et al, 2007;Aprahamian et al, 2011;Limani et al, 2016;Tran et al, 2019;Cao-Pham et al, 2020). The increases in regulated oxygen-releasing capacity of red blood cells has been shown to potentiate the response to irradiation (Teicher et al, 1998;Khandelwal et al, 1999;Amorino et al, 2001;Suh et al, 2006;Hou et al, 2007;Scott et al, 2007;Tran et al, 2019).…”

“…ΔR 1 and ΔR 2 * predictors of tumor oxygen evolution have been combined in a series of studies (Matsumoto et al, 2006;Winter et al, 2011;Burrell et al, 2013;Remmele et al, 2013;Hallac et al, 2014;Cao-Pham et al, 2020). Models were built thanks to combined measurements of ΔR 1 and ΔR 2 * in order to discriminate different regional responses to oxygen/carbogen breathing challenges, including normoxia, mild hypoxia, severe hypoxia or vascular steal (Cao-Pham et al, 2020;O'Connor et al, 2019).…”

“…ΔR 1 and ΔR 2 * predictors of tumor oxygen evolution have been combined in a series of studies (Matsumoto et al, 2006;Winter et al, 2011;Burrell et al, 2013;Remmele et al, 2013;Hallac et al, 2014;Cao-Pham et al, 2020). Models were built thanks to combined measurements of ΔR 1 and ΔR 2 * in order to discriminate different regional responses to oxygen/carbogen breathing challenges, including normoxia, mild hypoxia, severe hypoxia or vascular steal (Cao-Pham et al, 2020;O'Connor et al, 2019). While endogenous MRI contrast is particularly attractive due to non-invasiveness and large accessibility, clinical validation of ΔR 1 and ΔR 2 * remains the main goal to achieve for considering them as reliable biomarkers for tumor-hypoxia targeted treatments.…”