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Monitoring the Longitudinal Intra-tumor Physiological Impulse Response to VEGFR2 Blockade in Breast Tumors Using DCE-CT

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Abstract

Purpose

The purpose of this study was to quantify and model the longitudinal intra-tumor physiological response to a single dose of a monoclonal antibody specific to the VEGFR2 using dynamic contrast-enhanced CT.

Material and Methods

Dynamic contrast-enhanced CT imaging was performed on athymic nude mice bearing xenograft VEGF-transfected MCF-7 tumors (MCF7VEGF) to quantify intra-tumor physiology pre- and post-injection (days 2, 7, and 14) of a nonspecific (IgG1, controls) and specific (DC101, treated) monoclonal antibody targeting VEGFR2. Parametrical maps of tumor physiology—perfusion (F), permeability surface area (PS), fractional plasma (f p), and interstitial space (f is)—were obtained at four time points over a 2-week period.

Results

A temporal multistage recovery process whereby a decoupling of the fractional change in physiological parameters (f p, F) was observed when comparing treated to control tumors: f p and perfusion decreased by a combined 27% (P < 0.01) and 65% (P < 0.01) on day 2, while only perfusion remained reduced by 46% (P < 0.01) on day 7. Intra-tumor heterogeneity defined by the change in variance of perfusion decreased on days 2 and 7; no change in the variance of f p was observed. Analysis based on a mathematical model linking perfusion and vascular morphology indicates that a decrease in f p and perfusion was consistent with a reduction in blood vessel radius, followed by an increase in the vascular radius and tortuosity resulting in the decoupling of f p and perfusion before returning to control levels.

Conclusion

Inhibiting VEGFR2 activity results in a temporal decoupling of physiological parameters, which can be explained by a combination of morphological changes influencing perfusion. Such a decoupling has the potential to significantly impact the delivery of pharmaceuticals and oxygen within solid tumors, critical factors in combined anti-angiogenic and radio- and chemotherapies.

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Acknowledgments

This work was supported in part by the Indiana Genomics Initiative. The Indiana Genomics Initiative is supported in part by the Lilly Endowment.

Conflict of Interest

The authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. School of Health Sciences; Division of Medical Physics, Purdue University, 550 Stadium Mall Drive, West Lafayette, IN, 47907-2051, USA

    Keith M. Stantz, Minsong Cao & Ning Cao

  2. Department of Radiology and Imaging Sciences, Indiana University School of Medicine, 950 W. Walnut Street, Indianapolis, IN, 46202, USA

    Keith M. Stantz & Yun Liang

  3. Department of Radiation Oncology, Indiana University School of Medicine, 535 Barnhill Drive, RT 041, Indianapolis, IN, 46202-5289, USA

    Minsong Cao

  4. Department of Hematology/Oncology, Indiana University School of Medicine, 535 Barnhill Drive, Indianapolis, IN, 46202-5289, USA

    Kathy D. Miller

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  1. Keith M. Stantz
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Correspondence to Keith M. Stantz.

Additional information

Significance: DCE-CT provides a way to concurrently quantify four physiological parameters with high temporal and spatial resolution, and to do so longitudinally as a tumor progresses or in response to therapy. Few studies, if any, have systematically quantified the intra-tumor physiological response at various time points after a single dose of therapy has been applied, whether it is anti-angiogenic, radiation, or chemotherapy. To date, clinical doses are chosen to maximize therapeutic efficacy. These doses have been shown to significantly impact tumor biology and physiology, which can lead to adaptive responses associated with therapeutic resistance and metastasis. In this manuscript, DCE-CT was developed and used to quantify changes in tumor perfusion and vascular plasma volume over a couple of weeks after receiving a single cytostatic dose of DC101 relative to a nonspecific antibody. These set of experiments demonstrate an initial vascular response and a time-dependent recovery of vascular growth followed by perfusion. By studying the heterogeneous hemodynamic status of the tumor prior to and longitudinally after AAT, DCE-CT can be used to determine the optimal time and dose between anti-angiogenic and cytotoxic therapies and the time between successive combined anti-angiogenic plus cytotoxic therapies.

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Stantz, K.M., Cao, M., Cao, N. et al. Monitoring the Longitudinal Intra-tumor Physiological Impulse Response to VEGFR2 Blockade in Breast Tumors Using DCE-CT. Mol Imaging Biol 13, 1183–1195 (2011). https://doi.org/10.1007/s11307-010-0441-7

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