EVALUATION OF ANTIANGIOGENIC THERAPY OF BREAST CANCER USING PARACEST MRI

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Breast cancer continues to be the second leading cause of cancer deaths in American women according to American Cancer Society statistics for 2004. This highlights the need for research in breast cancer detection techniques to facilitate detection and treatment at an early stage in the disease. A detection technique with high sensitivity and specificity would also decrease the current high rate of negative biopsies of women with breast masses and help tailor individualized therapeutic options. Magnetic resonance imaging (MRI) of the breast enhanced with conventional, T1 altering, small molecular contrast agents have a high sensitivity for breast cancer detection but a limited specificity for characterization of the detected lesions. Conventional macromolecular contrast agents have the potential to provide this tissue differentiation but the sensitivity is low. One cannot use these two types of agents together as it would be impossible to distinguish between effects of the two. A novel class of paramagnetic contrast agents based on the chemical exchange saturation transfer (CEST) effect has been recently proposed for MRI applications. This new class of "PARACEST" contrast agents needs to be urgently evaluated in vivo especially since the theoretically predicted sensitivity of these agents is higher than conventional Gd-based agents. Due to its very low T1 relaxivity compared to Gd-DTPA, its administration will not affect a Gd-DTPA study performed on the same subject subsequently. Specific hypotheses to be tested during this project are: 1) PARACEST agent albumin-Eu-DOTA-4Am-(Gly)2(OBz-Ser)2 will display the theoretically predicted dependence on concentration in saline phantoms, 2) the PARACEST agent will not affect the relaxivity of Gd-DTPA, 3) Dynamic PARACEST contrast enhancement (DPCE) will be observed in vivo in rat breast tumors, 3) DPCE will allow extraction of tissue parameters such as endothelial permeability KPS and fractional plasma volume fPV and 4) Combining DPCE and DCE will allow prognostic evaluation of anti-angiogenic therapy in rat breast tumors. We will test our hypotheses using the following steps.1) Determine optimal MRI protocols to detect maximum contrast enhancement in saline phantoms of albumin-Eu-DOTA-4Am-(Gly)2(OBz-Ser)2. 2) Measure concentration dependence of MR image contrast and compare with theory. 3) Test the effect of the presence of PARACEST agent on the relaxivity of Gd-DTPA. 4) Perform in vivo MRI studies in rat breast tumors detect PCE and to follow kinetics over the time course. 5) Extract the vascular characteristics KPS and fPV from DPCE data using standard pharmacokinetic model. 6) Compare DPCE and DCE response to antiangiogenic therapy consisting of metronomic scheduling of cyclophosphamide. This work serves to lay the groundwork for the use of a new class of MRI contrast agents in breast cancer diagnostics. In this project, we plan to combine the information obtained from contrast kinetics of macromolecular PARACEST agent in rat tumors and with that from standard Gd-DTPA contrast agent kinetics. We, thus hope to combine the higher specificity and sensitivity of a macromolecular PARACEST agent with the high sensitivity of Gd-DTPA. We are hopeful that these sensitive agents will improve the specificity of detection of malignant lesions in breast cancer. This project requires the Research Resource for successful completion. PARACEST experiments will be performed in collaboration with Core 2 of the Research Resource and in close concert with Dr. Sherry's lab who synthesize the Europium agents. MR experiments will be performed with Center magnets and with the technical support of Center staff.