Breast cancer remains the second leading cause of cancer death in women and the primary cause of death in women ages 45 to 55, despite recent development of various therapies. Anti-angiogenic treatment approaches have been used as important means of treating cancer. However, optimization of such anti-angiogenic therapies for individual patients remains unresolved. Anti-angiogenics are thought to temporarily normalize abnormal vasculature and paradoxically increase blood flow and hence drug delivery to tumors. A substantial proportion of patients do not respond to this anti-angiogenic therapy but it is unclear whether the failure is due to failure of the anti-angiogenic to normalize the vasculature or failure of the cytotoxic to kill cells. It is therefore necessary to assess both blood flow and cell death to elucidate the mechanism and to monitor the efficacy of combined treatments. In this proposal we will investigate a single MRI acquisition and analysis that will allow assessment of both. Dynamic contrast enhanced (DCE) - MRI has emerged as a powerful tool for assessing tumor microcirculation environment. In this proposal we introduce a novel analysis method for DCE-MRI that combines the adiabatic approximation of tissue homogeneity model with a water exchange model (ATH-WX). This analysis provides estimates of both perfusion parameters (flow, vascular volume fraction, and vascular permeability-surface area product) and cell structural parameters (interstitial volume fraction, and intracellular water life time). The first stage of the study is comprised of a series of experiments to measure the association of the ATH-WX model parameters with other MRI and pathology measures during tumor growth. In the second stage, we will test out the proposed ATH-WX model for detection of early treatment response and compare its measures with pathology, in order to determine the ATH-WX parameters that best correlate with pathological changes induced by the therapy. In the third stage, we plan to apply the ATH-WX model to measure the anti-angiogenic effects of metronomic chemotherapy (MCT) in which a conventional cytotoxic drug is used to induce both anti-angiogenic and cytotoxic effects. In overall, the preclinical experimental data collected in this study will be used to test our main hypothesis that the proposed novel method (DCE-MRI with ATH-WX) can provide quantitative measures of both anti-angiogenic and cytotoxic responses simultaneously. The conclusion of this project will deliver a thoroughly tested noninvasive MRI method for quantitative measurement of tumor microenvironment. The proposed experiments in this application will lay important stepping stones toward utilizing this novel DCE-MRI method to improve patient management by allowing timely changes to ineffective treatment regimens. Since MRI is a ubiquitous and noninvasive method commonly used in modern medicine, the developed method in preclinical environment can be easily translated into a clinical tool for effective management of tumor treatment strategies.
Assessment of anti-angiogenic therapy, using either an anti-angiogenic targeted drug or a cytotoxic drug with metronomic schedule, requires an effective non-invasive method of measuring both the anti-angiogenic and cytotoxic effects of the therapies. Our underlying hypothesis is that a single dynamic contract enhanced MRI measurement using the adiabatic approximation of tissue homogeneity with water exchange (ATH-WX) model provides a means of assessing both anti-angiogenic and cytotoxic responses to anti-angiogenic therapies. The research in this proposal will establish an innovative method of assessing chemotherapy that will significantly improve drug discovery and patient management in a variety of cancers including breast cancer.
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