Early tumor detection is a critically important goal in oncologic imaging because it would enable treatment (or redirection of treatment) at earlier stages of disease. However, the challenge is imaging small collections of tumor cells because conventional in vivo imaging methods suffer from limited resolution and tumor contrast. MRI, which presents exquisite anatomical detail and many contrast mechanisms, still often proves incapable of detecting small clusters of tumor cells. Our strategy will be to develop a magnetic resonance imaging (MRI) agent with great amplification potential and to use magnetic resonance (MR) acquisition and image processing techniques to provide contrast sufficient to detect even very small tumors. Our proposal builds upon substantial preliminary data and brings together significant multi-disciplinary expertise in probe chemistry, tumor models, tumor biology, unique 3D microscopic cryo-imaging, advanced MR techniques, and quantitative image analysis. To date, we have discovered a novel molecular imaging strategy by targeting extracellular fragments of PTP? abundantly found in the tumor microenvironment;created mouse orthotopic models of gliomas;developed cryo-imaging methods to visualize and quantify tumor size, cell dispersal, white matter tracts and blood vessel density in 3D brain reconstructions;and discovered that a fluorescent PTP? probe quickly labeled main tumor as well as dispersed cells and even single migrating cells up to 3.5 mm away from the main tumor mass. Recently preliminary studies using a gadolinium conjugated PTP? probe indicate that we can see small tumors using MRI. We seek funding to demonstrate delineation of the dispersing tumor boundary and detection of tiny clusters of cancer cells using the PTP? molecular imaging probe by MRI. Even a skilled radiologist will not have the confidence to specifically diagnose a tumor until it is bigger than 5x5x5 mm3 even though typical spatial resolution is about 1x1x5 mm3 because of the non-specific, non-quantitative nature of the MR signal. Our approach will be to greatly increase contrast of the MR signal relative to background anatomical variations through amplification characteristics of PTP? MRI probe (PTP?-Gd), hardware, acquisition, and software improvements. We hypothesize that we can specifically identify and characterize tumors 2-3 orders of magnitude smaller than currently possible through the use of the PTP? molecular targeting agent combined with high resolution and quantitative MR.
The Specific Aims are: 1. Optimize and test the ability of the molecular PTP?-Gd probe to detect brain tumors in orthotopic xenografts and compare to "conventional" brain tumor MRI. 2. Determine the ability of PTP?-Gd to accurately image dispersing brain tumors as compared to gold-standard GFP-labeled tumor from microscopic cryo-imaging. 3. Optimize quantitative MRI using a clinically feasible (3T) dual-agent approach to test the limits for detecting small isolated brain tumors in a very highly dispersing tumor model.

Public Health Relevance

Small collections of tumor cells present a challenge to conventional in vivo imaging that suffers from limited resolution and tumor contrast and requires large anatomical changes to visualize tumors. Our strategy will be to develop a magnetic resonance imaging (MRI) agent with great amplification potential and to use MR acquisition and image processing techniques to provide contrast sufficient to detect tumors 2-3 orders of magnitude smaller than conventional imaging. We discovered a novel molecular imaging strategy based upon the recognition of an extracellular fragment of PTP? that is cleaved in the tumor microenvironment. Our fluorescent PTP? probe recognizes greater than 99% of all tumor cells including the main tumor, chains of tumor cells, small tumor cell clusters and even single migrating tumor cells in vivo in mouse intracranial xenograft glioma tumor models. Recent preliminary studies using a gadolinium conjugated PTP? probe indicate that we can see small tumors using MRI, which is a clinically relevant imaging modality. We seek funding to develop the PTP? molecular targeting agent combined with high resolution and quantitative MRI. Both software improvements and improved acquisition and processing proposed here will allow the specific targeting agent to be seen above the noise present in traditional non-specific MR images. The techniques developed will allow us to visualize streams of dispersing cells or small tumor foci, which are analogous to metastatic lesions in other tumor types.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
1R01CA179956-01
Application #
8589825
Study Section
Special Emphasis Panel (ZCA1-GRB-P (M1))
Program Officer
Farahani, Keyvan
Project Start
2013-09-01
Project End
2016-08-31
Budget Start
2013-09-01
Budget End
2014-08-31
Support Year
1
Fiscal Year
2013
Total Cost
$645,638
Indirect Cost
$230,637
Name
Case Western Reserve University
Department
Biochemistry
Type
Schools of Medicine
DUNS #
077758407
City
Cleveland
State
OH
Country
United States
Zip Code
44106
Craig, Sonya E L; Brady-Kalnay, Susann M (2015) Regulation of development and cancer by the R2B subfamily of RPTPs and the implications of proteolysis. Semin Cell Dev Biol 37:108-18