Purpose: Tumor angiogenesis drives unpredictable changes in blood perfusion and diffusion, which can have a major impact on tumor growth and metastasis. Anti-angiogenic drugs (AA) are designed to combat these effects, often by disrupting neovasculature formed during angiogenesis, but their therapeutic effects are poorly understood. In this work, we use photoacoustic CT spectroscopy (PCT-S) to assess the impact of various AA agents in syngeneic murine tumors.
Methods: Twenty-six immunocompetent mice were seeded with MMTV-PyMT tumor fragments and treated with one of four conventional AA agents (IgG4, DC101, Ang2, DC101-plus-Ang2) after growing to a volume of 250 mmÂ³. Seven days after treatment (3-treatments over 1-week), photoacoustic scans were acquired, sampling at ten NIR wavelengths. Longitudinal scans were acquired for individual tumors every 15 minutes over the span of two hours. PCT-S images were co-registered to assess regional changes in hemoglobin oxygen saturation (SaO2) over time.
Results: Longitudinal PCT-S data revealed intratumor regions of consistently low (chronic) and oscillating (acute) SaO2 in all tumors. All treatment groups observed comparable levels of acute hypoxia. DC101-treated tumors showed a slight elevation in normoxia (nss). Mice treated with Ang2 presented a significant increase in the abundance of chronic hypoxia relative to DC101, suggesting more-efficient disruption of neovasculature. Combination of DC101+Ang2 yielded a higher average chronically-hypoxic fraction than Ang2 alone, but this enhancement was not statistically significant.
Conclusion: Varying conventional AA agents induce distinct changes in the tumor microenvironment that can be measured using PCT-S. Spatial-temporal responses has the potential to discern vascular functional changes to different dose combinations. Histological analysis of hypoxia-specific factors (CA9, HIF2alpha) are currently being evaluated and will be presented.
Funding Support, Disclosures, and Conflict of Interest: This work was supported in part by Eli Lilly and Co.