In this project, the overall goal is to design novel molecular MRI methods that are minimally invasive or totally noninvasive and, as such, have a high potential of being translated rapidly into the clinic to be used for tumor assessment and monitoring of treatment. Towards this goal, we exploit so-called chemical exchange saturation transfer (CEST) contrast, which is generated through magnetic labeling of exchangeable protons (such as NH and OH) on either exogenous or endogenous agents, followed by a physical transfer (chemical exchange) of this label to water protons, which allows detection using MRI. To reach our ultimate goal of fast human translation, we will focus our efforts on diamagnetic, biodegradable, non-metallic compounds. Specifically, we will exploit the body's own building blocks, proteins and carbohydrates as CEST biomarkers and develop MRI technology to detect these markers. Tumors are generally characterized by an increased content of small mobile proteins and peptides, rapid glucose metabolism, and increased permeability between blood vessels and extravascular extracellular space. The overall goal therefore is to develop MRI pulse sequence technology and theory for detecting mobile protein content, glucose delivery and metabolism, and tumor perfusion.
Our first aim i s to assess protein content by employing nuclear interactions within these macromolecules (cross-relaxation) combined with the exchange ofthe protein's amide protons to water protons. In the second aim, glucose metabolism and tumor perfusion will be assessed by monitoring the uptake of non-labeled D-glucose using CEST. These technologies are expected to be applicable for most tumor types, but to demonstrate their applicability, we will apply them first to two human breast cancer lines: less aggressive (MCF-7) and highly aggressive and metastatic (MDA-MB-231). This will be done both ex vivo, in perfused cells and, in vivo, on xenografts in mice. As a third aim, we will perform pilot studies in patients to show feasibility of rapid translation.
These aims are expected to result in the availability of molecular MRI technologies in vivo that are suitable for immediate application in humans. Once established, we expect that these methods can be used for tumor detection, imaging tumor perfusion and metabolism, assessing tumor malignancy, and monitoring tumor treatment. This is expected to reduce false-positive detection rates by functioning as an add-on for current high-volume screening approaches and to improve treatment monitoring by MRI.

Public Health Relevance

Breast cancer is the most frequently diagnosed type of cancer in women and the second leading cause of death. Prevention, early diagnosis, and treatment are the three broad challenges for reducing mortality from breast cancer. In this project biocompatible MR technologies will be developed that can help to address the latter two clinical challenges using safe and practically noninvasive approaches.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Specialized Center (P50)
Project #
5P50CA103175-09
Application #
8728590
Study Section
Special Emphasis Panel (ZCA1-SRLB-9)
Project Start
Project End
Budget Start
2014-08-01
Budget End
2015-07-31
Support Year
9
Fiscal Year
2014
Total Cost
$311,305
Indirect Cost
$112,059
Name
Johns Hopkins University
Department
Type
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21218
Penet, Marie-France; Shah, Tariq; Bharti, Santosh et al. (2015) Metabolic imaging of pancreatic ductal adenocarcinoma detects altered choline metabolism. Clin Cancer Res 21:386-95
Ahn, Eun Hyun; Kim, Younghoon; Kshitiz et al. (2014) Spatial control of adult stem cell fate using nanotopographic cues. Biomaterials 35:2401-10
El Khouli, Riham H; Macura, Katarzyna J; Kamel, Ihab R et al. (2014) The effects of applying breast compression in dynamic contrast material-enhanced MR imaging. Radiology 272:79-90
Nimmagadda, Sridhar; Pullambhatla, Mrudula; Lisok, Ala et al. (2014) Imaging Axl expression in pancreatic and prostate cancer xenografts. Biochem Biophys Res Commun 443:635-40
Yadav, Nirbhay N; Xu, Jiadi; Bar-Shir, Amnon et al. (2014) Natural D-glucose as a biodegradable MRI relaxation agent. Magn Reson Med 72:823-8
Gadiya, Mayur; Mori, Noriko; Cao, Maria D et al. (2014) Phospholipase D1 and choline kinase-? are interactive targets in breast cancer. Cancer Biol Ther 15:593-601
Shamir, Eliah R; Pappalardo, Elisa; Jorgens, Danielle M et al. (2014) Twist1-induced dissemination preserves epithelial identity and requires E-cadherin. J Cell Biol 204:839-56
Huang, Peng; Ou, Ai-hua; Piantadosi, Steven et al. (2014) Formulating appropriate statistical hypotheses for treatment comparison in clinical trial design and analysis. Contemp Clin Trials 39:294-302
Subhawong, Ty K; Jacobs, Michael A; Fayad, Laura M (2014) Insights into quantitative diffusion-weighted MRI for musculoskeletal tumor imaging. AJR Am J Roentgenol 203:560-72
Zhu, Wenlian; Kato, Yoshinori; Artemov, Dmitri (2014) Water exchange-minimizing DCE-MRI protocol to detect changes in tumor vascular parameters: effect of bevacizumab/paclitaxel combination therapy. MAGMA 27:161-70

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