Tracking Pharmacodynamics of Vascular Targeted Therapy with Photoacoustic Imaging

Take-Away Points

• ■ Major Focus: To investigate feasibility of noninvasive photoacoustic imaging for quantifying pharmacodynamics of vascular-targeted therapy in tumors.

• ■ Key Result: Photoacoustic imaging measured time- and dose-dependent effects of an investigation of a vascular disrupting agent in two preclinical models of cancer.

• ■ Impact: Photoacoustic imaging can successfully monitor pharmacodynamics of tumor vasculature during therapy, supporting applications in drug development and clinical translation for precision medicine.

Imaging methods to analyze pharmacodynamics, the activity of a compound on its therapeutic target, potentially will increase development of new drugs for cancer and enable precision therapy for patients. Vascular disrupting agents represent a new class of anticancer compounds designed to target immature blood vessels typically associated with tumors. Success of these agents remains limited by a viable peripheral rim of cancer cells perfused by adjacent normal blood vessels and intertumor differences in susceptibility to hypoxia. Photoacoustic imaging, which uses low-intensity, nonionizing laser pulses to generate ultrasound waves for an image, provides an excellent method to image tumor blood vessels based on sensitive, high-contrast detection of hemoglobin. Using a high-resolution photoacoustic imaging instrument, Johnson et al measured the effects of the vascular disrupting agent OXi4503 in two different mouse models of colon cancer. In both models, photoacoustic imaging revealed initial ablation of internal blood vessels and subsequent regrowth of tumor vasculature over 16 days of treatment. For well-perfused tumors with extensive immature blood vessels, reductions in tumor blood vessels correlated highly with reductions in tumor volume over time. While poorly perfused tumors with larger, more mature blood vessels showed modest reductions in tumor blood vessels, changes in tumor vasculature did not predict effects on tumor volume. Treatment failures in poorly perfused tumors mirror past studies demonstrating resistance of such tumors to vascular disrupting therapy. Photoacoustic imaging also measured dose-dependent reductions in tumor blood vessels, establishing an approach to optimize doses and dosing schedules. These results establish photoacoustic imaging as a preclinical imaging method to advance development of vascular-targeted therapies. Furthermore, since photoacoustic instruments have entered clinical testing, this research supports future clinical applications of photoacoustic methods for pharmacodynamic imaging.

Highlighted Article

• Johnson SP, Ogunlade O, Lythgoe MF, Beard P, Pedley RB. Longitudinal photacoustic imaging of the pharmacodynamics effect of vascular targeted therapy on tumors. Clin Cancer Res 2019;25:7436–7447. doi: 10.1158/1078-0432.CCR-19-036