This revised competitive renewal seeks to extend the technical developments of the previous funding period to validate and apply a novel diffusion-based MR imaging technique, quantitative temporal diffusion spectroscopy (qTDS), that provides unique information on tissue microstructure and in particular can reveal early changes in tumors after treatment. In the previous cycle we developed this innovative method and showed it is a sensitive indicator of changes in cell dimensions and tissue microstructure such as those that occur with cell division and during apoptosis, before frank changes occur in cell density or tumor volume. As such, qTDS has considerable potential for assessing whether specific treatment regimens are working, and so may inform the selection of optimal therapies for patients and the reduction of avoidable side-effects. QTDS is based on measurements of water diffusion rates over different time scales corresponding to different spatial dimensions. We have previously shown it can detect changes in intracellular structure and cell sizes and density, in cell cultures and in animal models, early in the course of a treatment and without some of the confounding factors that affect other diffusion techniques, such as changes in cell membrane permeability. We have performed theoretical analyses, computer simulations, and cell and in vivo animal studies, to understand the factors that affect qTDS measurements, and have implemented the first practical qTDS acquisitions on a human 3T scanner. In the current proposal we aim to extend our previous work and use qTDS as an in vivo imaging technique for non-invasive characterization of specific cellular changes which are currently assessable only via invasive biopsy. We propose to validate qTDS in cell and animal models of cancer, and determine whether qTDS is capable of detecting treatment-induced cell size changes early in specific therapeutic regimens. We also propose to translate qTDS clinically by demonstrating its performance in predicting neoadjuvant treatment response in breast cancer. We hypothesize that qTDS is capable of characterizing the distinct cellular changes associated with treatment-induced apoptosis, thereby providing an innovative and unique means of assessing tumor response at an early stage of therapy.
Our specific aims are: [i] in a transgenic mouse model of breast cancer, we will quantitatively map tumor cell size and density in vivo, and validate the qTDS derived parameters on a voxel by voxel basis using using quantitative, co-registered histology: [ii] in mouse models of breast cancer treated by different targeted drugs, we will evaluate qTDS as an imaging biomarker capable of detecting treatment-induced apoptosis and predicting treatment efficacy early during therapy: [iii] In human breast cancer patients, we will evaluate qTDS as an imaging biomarker for assessing breast tumor early response to neoadjuvant chemotherapy and predicting treatment efficacy after the first and subsequent cycles of treatment by correlating imaging data with clinical and pathological responses. The proposed qTDS method has the potential to measure cell size changes in vivo and improve the assessment of treatment response and thereby contribute to personalized clinical cancer care.

Public Health Relevance

This proposal aims to validate and apply a novel MRI imaging technique based on measuring the diffusion of water molecules in water over different time scales, from which unique information on tissue microstructure such as cell size and density can be derived. The method is well suited to assess the early response of tumors to treatment and thus to play a currently unfulfilled role in the management of cancer patients. The method will be applied in an ongoing clinical trial of breast cancer therapy and in parallel studies will be validated by studies in mice that will aid the interpretation of the imaging data.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Medical Imaging Study Section (MEDI)
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Zhang, Huiming
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Vanderbilt University Medical Center
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By, Samantha; Xu, Junzhong; Box, Bailey A et al. (2018) Multi-compartmental diffusion characterization of the human cervical spinal cord in vivo using the spherical mean technique. NMR Biomed 31:e3894
Zhang, Xiao-Yong; Wang, Feng; Xu, Junzhong et al. (2018) Increased CEST specificity for amide and fast-exchanging amine protons using exchange-dependent relaxation rate. NMR Biomed 31:
Zu, Zhongliang; Li, Hua; Xu, Junzhong et al. (2017) Measurement of APT using a combined CERT-AREX approach with varying duty cycles. Magn Reson Imaging 42:22-31
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Tian, Xin; Li, Hua; Jiang, Xiaoyu et al. (2017) Evaluation and comparison of diffusion MR methods for measuring apparent transcytolemmal water exchange rate constant. J Magn Reson 275:29-37
Zhang, Xiao-Yong; Xie, Jingping; Wang, Feng et al. (2017) Assignment of the molecular origins of CEST signals at 2?ppm in rat brain. Magn Reson Med 78:881-887
Zhang, Xiao-Yong; Wang, Feng; Li, Hua et al. (2017) Accuracy in the quantification of chemical exchange saturation transfer (CEST) and relayed nuclear Overhauser enhancement (rNOE) saturation transfer effects. NMR Biomed 30:
Zu, Zhongliang; Louie, Elizabeth A; Lin, Eugene C et al. (2017) Chemical exchange rotation transfer imaging of intermediate-exchanging amines at 2 ppm. NMR Biomed 30:
Zhang, Xiao-Yong; Wang, Feng; Jin, Tao et al. (2017) MR imaging of a novel NOE-mediated magnetization transfer with water in rat brain at 9.4?T. Magn Reson Med 78:588-597
Jiang, Xiaoyu; Li, Hua; Xie, Jingping et al. (2017) In vivo imaging of cancer cell size and cellularity using temporal diffusion spectroscopy. Magn Reson Med 78:156-164

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