Network for Translational Research (NTR): Optical Imaging in Multimodality Platforms

Network for Translational Research (NTR): Optical Imaging in Multimodal Platforms (U54)({RFA-CA-08-002) Request for Applications 1 The Network for Translational Research (NTR): Optical Imaging in Multimodal Platforms is a reissue of the former Network for Translational Research in Optical Imaging (NTROI).  Rather than focusing on a single optical modality for imaging a cancer problem as the former NTROI did, this new NTR program now emphasizes imaging based on multiple modalities, one of which is an optical method.  The purpose of the network is the development, optimization, and validation of imaging methods and protocols for rapid translation to clinical environments.  Optimization and validation are accomplished through consensus processes. This network is one of several being conducted within the Cancer Imaging Program.  The hallmark of this NTR network is its emphasis on early-stage imaging technology.  By combining optical methods with more traditional imaging techniques, it is anticipated that the optical methods can be brought more quickly to clinical trials where they can become competitive with the other imaging methods. Four centers of imaging excellence have been selected through the NIH peer review process.  A Steering Committee, consisting of two investigators from each center plus various program staff from the NCI, has oversight of the network.  Click here to see the Steering Committee membership 2.  This committee meets monthly via teleconference and organizes network-wide activities such as consensus publications, cross-network core activities, associate membership in the network, and semi-annual face-to-face meetings. The organization of the NTR is more than just an assembly of four separate research programs.  Click here to read about the Network Organization 3.  In addition to the Steering Committee, the four centers are linked by Research Support Cores.  These are functions identified by the centers as being common to each center.  By pooling resources in these areas, the centers can leverage their resources and prevent “siloing”, a common problem in many multi-site initiatives.  Click here to read about the five Research Support Cores 4. NTR Funded Centers Washington University 5 Lihong Wang, Ph.D. (lhwang@biomed.wustl.edu 6) Photoacoustic/Optical/Ultrasonic Imaging of Sentinel Lymph Nodes and Metastases.  <http://ntroi.wustl.edu/>Web site University of Texas Health Science Center, Houston 7 Eva Sevick, Ph.D. (eva.sevick@uth.tmc.edu 8) Diagnostic Nodal Staging with Nuclear and NIR Molecular Optical Imaging.   <http://www.uthouston.edu/imm/centers/molecular-imaging.htm>Web site University of Michigan 9 Thomas D Wang, M.D., Ph.D. (thomaswa@umich.edu 10) In vivo Detection of Neoplasia in the Digestive Tract.  <http://sitemaker.umich.edu/ntr/home>Web site Stanford University 11 Christopher Contag, Ph.D. (ccontag@cmgm.stanford.edu 12) Multimodal Imaging of GI Cancers for Diagnosis and Directed Therapy.  <http://ntroi.stanford.edu>Web site

Photoacoustic/Optical/Ultrasonic Imaging of Sentinel Lymph Nodes and Metastases.
Lihong Wang, Ph.D.
lhwang@biomed.wustl.edu ⁶
Washington University, St. Louis

http://ntroi.wustl.edu/>Web site

Grant Number: U54CA136398

The primary goal for the Washington University NTR Research Center is to provide and validate a multimodal imaging platform as a novel real-time clinical imaging tool for sentinel lymph node mapping and axillary staging. Sentinel lymph node biopsy (SLNB) has become the standard method of axillary staging for patients with breast cancer and clinically negative axillae. The ability to identify the SLN noninvasively in vivo would be a highly useful clinical tool for breast cancer patients, as it would enable the clinician to identify the SLN in vivo so that non-invasive diagnostic methods (e.g., fine needle aspiration biopsy and reverse transcription polymerase chain reaction) could be utilized to stage the axilla without the morbidity of an operative procedure.

The proposed imaging tool, photoacoustic tomography, is a hybrid technology that can be used in combination with conventional ultrasound imaging. Ultrasound will be used to image lymph nodes--which are hypoechoic, whereas photoacoustic imaging will be used to identify sentinel nodes which will be indicated by accumulated methylene blue dye. As opposed to ultrasound, which cannot detect methylene blue dye, photoacoustic imaging has high sensitivity to methylene blue dye due to strong optical absorption contrast. The primary project will therefore test the hypothesis that photoacoustic imaging can reliably map human sentinel lymph nodes using methylene blue contrast.

The specific aims are to
(1) Develop a laser light delivery system,
(2) Adapt a clinical ultrasound imaging system for photoacoustic and ultrasonic imaging, and
(3) Establish performance of PAT by image axillary lymph nodes in humans.
The task-specific projects and center cores will enhance photoacoustic imaging with additional capabilities including molecular imaging. The extended clinical goal will be to provide comprehensive non-invasive multi-modal imaging for SLN mapping, metastasis detection and breast cancer management. Toward this goal, incorporation of molecular contrast agents will be developed to enhance sensitivity and specificity and provide a strategy for multimodal validation.

Diagnostic Nodal Staging with Nuclear and NIR Molecular Optical Imaging.
Eva Sevick-Muraca, Ph.D.
eva.sevick@uth.tmc.edu ⁸
University of Texas Health Science Center, Houston

http://www.uthouston.edu/imm/centers/molecular-imaging.htm>Web site

Grant Number: U54CA136404

The primary project is to focus upon translation of imaging agents and devices developed at The Baylor College of Medicine (BCM) and translated in Phase I studies at The Michael E. DeBakey Veterans Administration Medical Center (MEDVAMC) as well as at Ben Taub General Hospital (BTGH). Dual labeled imaging agents for nuclear and fluorescence imaging will be produced under the BCM and LI-COR expertise in the Chemistry Core; imaged with near-infrared (NIR) fluorescence imaging and tomography devices built and algorithms written in the Instrumentation and Tomography Task Specific Projects; and approved following combinational FDA applications developed with safety and toxicity data generated in the Preclinical Testing Core. Initially we will translate two established agents which target (i) cancer cells within the lymphatic space and (ii) the reorganization of the stromal lymph node compartment as a hallmark of tumor malignancy in both breast cancer and melanoma patients. The results from Task Specific Projects that successfully validate additional candidate imaging agents will then be fed into the infrastructure of the primary project to conduct Phase 1 and Phase I/I I studies demonstrating nodal staging in Nuclear Medicine, intra-operative guidance for lymph node removal, and accurate molecular pathology. Provisions for including other consortia members are "build into" the infrastructure of the network for nodal staging of cancer.

This Network for Translational Research builds upon over a decade of development of
(i) NIR conjugates for cancer targeting,
(ii)novel instrumentation for time-dependent measurement of fluorescence in deep tissues, and
(iii) innovative algorithms which enable non-contact imaging and integration with nuclear imaging modalities.

In vivo Detection of Neoplasia in the Digestive Tract. 
Thomas D. Wang, M.D., Ph.D.
thomaswa@umich.edu ¹⁰
University of Michigan

http://sitemaker.umich.edu/ntr/home>

Grant Number: U54CA136429

The University of Michigan has established an international, multi-disciplinary, multi-institutional Center in the Network for Translational Research (NTR) to develop standardize, validate, and optimize a targeted, multi-modal optical/nuclear imaging platform. This integrated imaging strategy uses labeled molecular probes to identify pre-malignant mucosa in the digestive tract for the early detection of cancer. This methodology has been developed to addresses an important unmet clinical need for improved detection of flat dysplasia that lacks architectural changes and goes undetected on surveillance endoscopy. Peptides are being developed for use as targeting agents because of their high diversity, small size, flexibility in labeling and minimal immunogenicity, and are well-suited for clinical use because of their rapid binding kinetics, deep tissue penetration and lack of toxicity.

The goal of the Primary Project is to establish the network infrastructure, standardize the imaging protocols and validate imaging performance. The detection of dysplasia with affinity peptides is performed in a systematic fashion. First, macroscopic imaging with PET/SPECT/CT localizes regions of disease in specific anatomic segments in the digestive tract with complete co-registration. Then, minimally invasive methods of mesoscopic imaging with fluorescence endoscopy are performed to directly visualize the spatial extent of the local targeted region over the large surface areas found in hollow organs. Finally, microscopic imaging with confocal techniques provides virtual histology to validate the pre-malignant lesions using quantitative criteria on optical sections.

We have combined the strengths and resources from academia, including the University of Michigan, Mayo Clinic, University of Washington, and VA Palo Alto, and industry, including Olympus Medical Systems Corp, GE Healthcare, Mauna Kea Technologies, and STI Medical Systems Inc, to establish a world class team of investigators to pursue these aims.

Phase 1 and 2 clinical studies will be performed to demonstrate the safety and efficacy of this novel, integrated imaging strategy. The results will then be used to plan a future multicenter clinical trial to begin at the end of the funding period. In addition, key needs in the Primary Project are being addressed by four Task-Specific Projects. The aims of the projects funded in year 1 include:
1) to develop radio-labeled peptides to localize dysplasia on PET/SPECT/CT in a CPC;APC mouse model of colon cancer;
2) to demonstrate vertical cross-sectional imaging with sub-mucosal tissue penetration depths using a miniature dual axes confocal microscope;
3) to select and validate peptides that affinity bind to high-grade dysplasia in Barrett's esophagus;
4) to develop a miniature scanning fiber endoscope for wide area surveillance in the bile and pancreatic ducts.

Multimodal Imaging of GI Cancers for Diagnosis and Directed Therapy.
Christopher Contag, Ph.D., Principal Investigator
ccontag@cmgm.stanford.edu ¹²
Stanford University

http://ntroi.stanford.edu>Web site

Grant Number: U54CA136465

Understanding and controlling the transition from dysplasic growth to neoplasia in the gastrointestinal tract requires coordinated evaluation of the molecular and anatomic markers of disease using both specific biochemical probes to recognize alterations in cellular physiology and cell surface markers, and established technologies that can detect and interrogate both structure and function. To improve detection of Gl cancers we plan to perform collaborative translational research in optical imaging and spectroscopy using multimodal platforms for the detection of early neoplastic lesions arising from the Gl epithelium.

We have established an integrated Specialized Research Resource Center comprised of investigators from Stanford University, Vanderbilt University, University of Florida and University of California, Davis. The overarching aim of this program is develop a consensus process and methodology based on optics and ultrasound to optimize detection of early molecular markers of disease by examining molecular markers in the context of ultrastructural changes.

We are using fluorescence contrast agents for functional analyses and both optics and ultrasound for assessing anatomic changes. Aided by wide-field fluorescence endoscopy and ultrasound, fiberbased optical probes are being used to analyze the molecular signatures of disease. The engineering components of this program are aimed at systems integration using established white light/fluorescence endoscopy and ultrasound systems and state-of-the-art miniaturized sensors for high resolution/high sensitivity detection of molecular probes directed at markers of cancer. The probe chemistries are well-established and based on existing targets. Probes include peptides, selected for binding to dysplastic epithelium, and compounds directed at COX-2 as an intracellular marker of malignancy.

The program provides an infrastructure to support subprojects that are aimed at translating well-developed tools and techniques into the clinic. In each subproject, a strong foundation of established technologies supports innovative approaches to improve integration and enhance early detection. The clinical team consists of endoscopists with a track record of translational research who will evaluate the integrated tools and reagents in patients. We have a strong pathology team comprised of pathologists with expertise in optical imaging and spectroscopy to facilitate validation with histopathological standards.

The major project in this program has four specific aims that are each addressed in a multidisciplinary and directed approach. These include: i) validation of molecular markers of Gl cancer as targets for imaging and therapy,
ii) advancing molecular probes and integrated instrument combinations for imaging and therapy of Gl cancer,
iii) optimization of probe-therapy combinations based on validated molecular markers, and
iv) clinically evaluate instrument and probe combinations.
These aims are supported by two task specific projects and 5 cores with oversight by an executive committee.

NTR Research Support Cores

The NTR is linked at several levels. A Steering Committee ² has governance oversight of the network. While this provides the administrative coordination and communication points of contact between program staff and the individual centers, the Steering Committee does not engage in technical issues that are common to all centers. This is the function of the individual Research Support Cores.

These Cores provide cross-network coordination in five different areas:

Back to Network Organization ³

NTR Network Organization

The map below shows the geographical locations of the four network centers and the ways in which they are linked together. Both the Stanford Center and the University of Michigan Center are doing research in the gastrointestinal tract. Optical molecular probes are a main focus of both centers, and confocal imaging is being used. However, the Stanford team is pairing the optical technologies with miniaturized ultrasound to augment their imaging capabilities, while the University of Michigan center is using nuclear imaging as a way to validate the optical imaging results.

The University of Texas Health Science Center and Washington University are each studying identification and staging of breast sentinel lymph nodes. The Washington University center has chosen to bring ultrasound imaging together with the optical method of photoacoustic imaging, and the University of Texas Health Science Center is uniting optical fluorescence method with nuclear imaging.

The result is an exciting linkage of organ sites and imaging technologies that is yielding a high degree of cooperation and coordination within the network. While two sites are focused on the GI tract and the other two are focused on breast lymph nodes, there is a cross-over in the imaging methods used. In two sites, ultrasound is being paired with optical methods, while in the other two sites nuclear techniques are paired with the optical methods.

At the base of the network organization is the Research Support Cores. These functions link the four centers by providing advances and decision-making common to all four centers. Click here to read about the Research Support Cores.