CP #2: Distinguishing Antiangiogenic From Cytotoxic Effects with DCE-MRI and MR-PET

Distinguishing Antiangiogenic From Cytotoxic Effects With DCE-MRI and MR-PET

Significance:

Despite ongoing development of new cancer treatments, breast cancer remains the most common cancer found in women as well as the leading cause of death in women between the ages of 45 and 55 [1,2]. A promising treatment strategy that combines cytotoxic drugs with anti-angiogenic drugs has been developed to treat Locally Advance Breast Cancer (LABC) [3,4]. In this treatment, the anti-angiogenic component temporarily normalizes the vascular structures in the tumor, which allows for improved transport and delivery of the cytotoxic drugs [5-8]. Unfortunately, a substantial proportion of patients do not respond to this treatment, and it is unclear if this is due to failure of the anti-angiogenic or of the cytotoxic effect [9,10].By applying a novel pharmacokinetic model for dynamic contrast enhanced (DCE) MRI that combines the adiabatic tissue homogeneity model [11,12] with a water exchange model (ATH-WX, Figure 1) [13-19], we can provide an accurate description of blood and tissue water dynamics. ATH-WX analyses of DCE-MRI provide estimates of flow, F, and vascular permeability-surface area product, PS, as separate entities rather than using the vascular transfer constant, Ktrans, which is a function of both F and PS. The ATH-WX model involves fitting of both perfusion parameters (flow, F, vascular volume fraction, Vb, and vascular permeability-surface area product, PS) and cellular parameters (interstitial volume fraction, Ve, and intracellular water life time, ti).  Thus, it is well positioned to make the critical distinction between antiangiogenic and cytotoxic effects. 

Aims:

In this study, we will determine the ATH-WX parameters that best correlate with anti-angiogenic and/or cytotoxic effects of VEGF-targeted therapies in the 4T1 mouse model.

Approach:

The ATH-WX model will be tested with BALB/c mice with 4T1 mouse mammary tumor, which closely resembles human breast cancer in terms of its aggressiveness and high metastasic potential [20-23]. There will be four groups (control, cyclophosphamide (CTX) treated, bevacizumab treated, and simulatanous CTX and bevacizumb treated) of 40 female BALB/cJ mice with matched size (~ 7 mm in diameter) of subcutaneous 4T1 tumors. MRI will be conducted four times; immediately before treatment, and on days 1, 7, and 14 post-treatment.  A Bruker 7T animal scanner with a Paravision console will be used. DCE-MRI scans will be conducted using the GRASP method developed in TRD #1, suitably modified for animal scanning, in order to achieve both high temporal and high spatial resolution. A bolus of 10 mM Gd-DTPA in saline, corresponding to dose 0.1 mmole/kg, will be injected through a tail vein catheter starting after the acquisition of 1-min pre-contrast images followed by 9-min post-contrast images. Histological studies will be performed to quantify cell density, vascular density, proliferation and tumor cell killing.

Push-Pull Relationship with TR&D Projects 1 & 3: 

TR&D#1: This collaborative project relies upon DCE-MRI, which involves continuous acquisition of a large vol­ume of data. A successful DCE-MRI study requires a high spatial resolution to probe tumor heterogeneity and a high temporal resolution to adequately capture the fast bolus passage through the circulatory system as well as rapid enhancement characteristics of the tumor. These two stringent requirements become even harder to meet in mouse imaging where MRI studies are often limited by small voxel size. The rapid volumetric com­pressed sensing and parallel imaging techniques developed in TR&D#1 represent crucial enablers of the pro­posed studies in this CP. At the same time, stringent requirements from this CP will push TR&D #1 to produce practical solutions for the spatial and temporal scales associated with small animal imag­ing.

TR&D#3: For cross-validation of ATH-WX parameters in animal and eventually human studies, this CP will drive production of 18F-FLT as a cellular proliferation marker and 18F-RGD-K5 as an angiogenesis marker.  The CP will also drive BTRC staff to include ATH-WX in the joint MR-PET kinetic modeling framework of Aim 3.

Principal Investigator: 

Sponsors

Latest Updates

10/31/2017 - 11:54
10/31/2017 - 11:37

Philanthropic Support

We gratefully acknowledge generous support for radiology research at NYU Langone Medical Center from:
 
• The Big George Foundation
• Raymond and Beverly Sackler
• Bernard and Irene Schwartz

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