Monitoring Changes of the Tumor Microenvironment Following Administration of a Novel Vascular Disrupting Agent OXi6197 Using Multi-parametric MRI

Heling Zhou¹, James Campbell¹, Zhang Zhang², Debabrata Saha², Rebecca Denney¹, Mary Lynn Trawick³, Kevin G Pinney³, and Ralph P Mason¹

¹Radiology, UT Southwestern Medical Center, Dallas, TX, United States, ²Radiation Oncology, UT Southwestern Medical Center, Dallas, TX, United States, ³Chemistry and Biochemistry, Baylor University, Waco, TX, United States

Synopsis

Vascular disrupting agents (VDAs), selectively damage the endothelial cells of tumor blood vessels, inducing ischemia and consequent hypoxia and cell death. We investigated the impact of a novel indole-based VDA (OXi6197) to tumor perfusion and oxygenation using multi-parametric MRI on a lung tumor animal model. DCE MRI showed decreased blood flow after administration of VDA. Oxygen sensitive MRI, BOLD and TOLD, showed progression of hypoxia at 24 hours. Multimodality imaging provides useful information to evaluate the efficacy of VDA. The findings in this study will be important for dose optimization and potential combination therapy in the future.

Purpose

Vascular disrupting agents (VDAs) have attracted much interest and show promising therapeutic results. However, it is recognized that VDAs will likely be used in combination with additional therapy such as radiation. VDAs induce ischemia, which leads to hypoxia and cell death ¹, which is an important factor to consider particularly for combination with radiation. Here, we investigated the impact of a novel VDA (OXi6197, a dihydronaphthalene-based VDA structurally inspired by combretastatin A-4 phosphate (CA4P) and colchicine) on tumor perfusion and oxygenation using multi-parametric MRI of lung cancer animal models.

Methods

A549 human lung cancer cells were implanted in the thigh (subcutaneously) of nude rats (pre-treated with whole body radiation). MRI was performed at 4.7 T including interleaved BOLD (blood oxygen level dependent R₂*: multi-echo gradient echo) and TOLD (tissue oxygen level dependent T₁w: gradient echo) with respect to an oxygen challenge (from air to 100% O₂). T₁ maps (spin echo) were acquired while breathing air and oxygen. With continued oxygen breathing DCE-MRI (dynamic contrast enhanced) was performed with IV injection of gadolinium contrast (Gadavist; 0.1 mmol/kg). OXi6197 was administrated IP (15 mg/kg). Multi-parametric MRI was repeated 24 hours later. Data were processed using Matlab. Semi-quantitative percentage signal intensity changes (%ΔSI) of BOLD and TOLD and quantitative T₁ and T₂* maps were calculated. Area under the curve (AUC), time-to-maximum (TTM) and slope were calculated from DCE-MRI. A reference tissue model was used for the quantitative analysis to obtain K^trans and v_e ².

Results and Discussion

Oxygen-sensitive MRI showed progression of hypoxia 24 hours after administration of the VDA, OXi6197 (Figure). Tumor T₂* baseline decreased (from 14.3±5.5ms to 9.7±3.0ms) suggesting more deoxy-hemoglobin, while muscle showed much less change (from 12.9±2.0ms to 11.1±2.1ms). The observation is consistent with decrease of perfusion after VDA, revealed by MIP (decreased by 21%), AUC (decreased by 33%) and slope (decreased by 42%). Muscle on the other hand, showed minimal changes (MIP: 6%; AUC: 5%; slope: -3%). Maximum signal enhancement was observed after a significantly longer time especially for the central tumor regions. Ktrans and ve didn’t show consistent changes after receiving VDA.

Conclusions

DCE-MRI showed decreased perfusion after administration of the VDA, OXi6197. T₂* values decreased 24 hours after receiving the VDA, which may imply increased deoxy-hemoglobin in the tumor.

Acknowledgements

The study was supported in part by R01 CA140674, 1P30 CA142543 and P41 EB015908.

References

1. Mason, R.P., D. Zhao, L. Liu, M.L. Trawick, and K.G. Pinney, A perspective on vascular disrupting agents that interact with tubulin: preclinical tumor imaging and biological assessment. Integr. Biol., 2011. 3(4): p. 375-387.

2. Faranesh, A.Z. and T.E. Yankeelov, Incorporating a vascular term into a reference region model for the analysis of DCE-MRI data: a simulation study. Physics in medicine and biology, 2008. 53(10): p. 2617-2631.

Figures

Multi parametric MR images showing tumor physiological changes following the IP injection of the VDA in a representative animal. Significant decrease in oxygenation is suggested by both BOLD and TOLD oxygen breathing challenge response maps consistent with the decrease of T₂* and increase of T₁ values. Label shown on T₂W: T – Tumor; M – Muscle; B – Bone marrow; S – Spine.

Proc. Intl. Soc. Mag. Reson. Med. 24 (2016)

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