The Network for Translational Research: Optical Imaging (NTROI) Request for Applications ¹ was structured to support three or more multi-site teams that would include broad national and international representation from academia, NIH intramural, and device and drug industry investigators. The Network develops consensus processes for translational research, including optimizing emerging optical imaging systems, targeted or activatible probes, and validations. Long-term goals include development and delivery of common or similar platforms for measuring and extracting quantitative signatures from endogenous molecules or molecular probes that are cancer specific. Use of combined signatures will improve sensitivity and specificity particularly for early cancer detection, cancer diagnosis, treatment and measurement of response to therapy.

A Network Steering Committee (SC) of team principal investigators and key co-investigators also includes scientific observers from the Food and Drug Administration, National Science Foundation, and National Institute of Standards and Technology to encourage a more transparent and timely process for regulatory approval of optical imaging methods.

The response to this published RFA was much greater than our early expectations. Optical and optical molecular imaging is the fastest growing imaging modality for cancer research. The timing of this network is therefore critical, best exercised during this early phase of development to bring the different communities together to accelerate delivery of these technologies. It is a timely model for leveraging investigator initiated funded projects that support the technology platforms.

This network's organizational structure with its Steering Committee provides a good model and a timely opportunity to explore public-private partnerships through the Foundation of NIH. Industry has already indicated significant interest in this network.

Several of the device and drug industries on the teams have developed Intellectual Property (IP) agreements with academia in advance of review, suggesting that validation methodology does not pose significant IP barriers, normally a problem for private-public partnerships for inventions.

NTROI Funded Projects

University of California, Irvine ²
Bruce Tromberg, Ph.D. (tromberg@laser.bli.uci.edu ³)
Breast Cancer Multi-Dimensional Diffuse Optical Imaging

Boston University ⁴
Irving Bigio, Ph.D. (bigio@bu.edu ⁵)
Optical Spectroscopy for Management of Cancer Treatment

University of Pennsylvania ⁶
Wafik El-Deiry, M.D., Ph.D. (wafik@mail.med.upenn.edu ⁷)
Network for Translational Research: Optical Imaging

Stanford University ⁸
Christopher Contag, Ph.D. (ccontag@cmgm.stanford.edu ⁹)
Detection of Neoplasia in the Esophagus

Breast Cancer Multi-Dimensional Diffuse Optical Imaging
Bruce Tromberg, Ph.D., Principle Investigator
tromberg@laser.bli.uci.edu ³
University of California, Irvine

Grant Number: 1U54CA105480-01

Participating Organizations

• Academic: University of California, Irvine, NIH Intramural Research, University of Pennsylvania, University of Illinois, Urbana-Champaign, Massachusetts General Hospital, Dartmouth Medical
• Industrial: Siemens Corp, Newport Corp, ISS Inc, ART Inc, General Electric
• Planned Associate Members: American College of Radiology Imaging Network, University of California, San Francisco, Food and Drug Administration, European Breast Cancer Consortium, Applied Photonics, SPIE - International Society for Optical Engineering

Modalities
Optical diffusion mammography, combined MRI-optical tomography systems, digital mammography, localized spectroscopy, broadband molecular imaging of multiple optical probe agents, data processing and computer aided diagnosis.

Clinical Impact
This team is set to validate and translate optical and multimodality approaches to breast cancer diagnosis, treatment, and treatment monitoring. They will leverage current-art imaging hardware at sites that include an NCRR P41Research Resource Center, 5 NCI Comprehensive Cancer Centers, Program Projects for breast cancer screening and diagnosis to be combined on a standardized platform supported by industry, with clinical evaluation at the five Comprehensive Cancer Centers. Methods include broadband molecular imaging of several optical probes, combined modalities (MRI/Optical) and data processing to improve specificity for breast cancer diagnosis and monitoring the response to hormone replacement and neo-adjuvant chemotherapy.

Strengths
Substantial participation by major cancer centers and business participants assure broadly based clinical validations and rapid dispersal to clinical application through marketed products. They present a thorough, comprehensive approach to melding several optical approaches with more established breast cancer imaging modalities with excellent prospects of improving sensitivity and greater gains in specificity and reduced false positives and false negatives.

Synergisms with Other Teams
They will provide a common platform for breast optical tomography. Several other teams have complementary projects for nodal assessments that could help this team, and this team would provide focused targets for their technologies.

Optical Spectroscopy for Management of Cancer Treatment
Irving Bigio, Ph.D., Principle Investigator
bigio@bu.edu ⁵
Boston University

Grant Number: 1U54CA104677-01

Participating Organizations

• Academic: Boston University, University College of London, University of Pittsburgh
• Industrial: Optimum Technologies, Chemical Operations (Pharmacyclics), DiametRx, Inc

Modalities
In vivo contact probe for Elastic Scattering Spectroscopy and "Optical Pharmacokinetics" (fast UV through IR analytical in vivo spectrophotometry).

Clinical Impact
This innovative modality delivers analytical (absolute value) photometric spectra from 300 to 1000 nm (UV to IR) from the volume of interest. This break-through development delivers 3 analytical spectral readings per second, enabling site-specific tracking of absolute values for pharmacokinetics of bolus-administered drug, optical agent, and biochemical changes in vivo. It can be readily stepped to new spots to sample differences due to tumor heterogeneity. Its rapid data rate permits dynamic tracking of drug accumulation, conversion and/or washout (pharmacokinetics and aspects of pharmacodynamics) as well as permit microvasculature permeability analyses for assessment of angiogenesis, and prompt and longer term effects of anti-angiogenesis therapy. Elastic Scattering Spectroscopy measures rapid and slow changes in tissue granularity (cell organelles), suitable to measure and track changes in nuclear density, structure and condition before, during and after therapy - potentially an important clinical management tool.

Strengths
Their approach brings some better features of bench-style analytical biochemistry and pharmacokinetics to the real-time in vivo environment. It should be able to see disseminated clinical applications by the end of 5 years. The probes can be adapted to endoscopy and laparoscopy.

Synergisms with Other Teams
Both analytical and elastic scattering spectroscopy can correlate with data from fluorescence, diffusion and scattering spectroscopy that are important features of the other Teams. The other teams can use the powers of this method for analytical validations of their approaches to in vivo measurements, e.g.,
(1) optical imaging of neo-adjuvant therapy and other approaches to breast cancer treatment in the 5 participating NCI Comprehensive Cancer Centers of the first NTROI team;
(2) lymphatic spread, nodal metastases, non-invasive imaging of angiogenesis, correlates to hypoxia, hypoglycemia, blood flow, and markers for therapeutic response and toxicity - foci of colon cancer studies by the third NTROI team.

Network for Translational Research: Optical Imaging
Wafik El-Deiry, M.D., Ph.D., Principle Investigator
wafik@mail.med.upenn.edu ⁷
University of Pennsylvania

Grant Number: 1U54CA105008-01

Participating Organizations

• Academic: University of Pennsylvania, Children's Hospital of Philadelphia, Fox Chase Cancer Center
• Industrial: LightForm Inc, 3-Dimensional Pharmaceuticals Inc, Morphotech Inc, Cell Pathways Inc, Cephalon Inc, 5Star Medical Inc, Versilant Nanotechnologies, NIM Inc

Modalities
Bioluminescent probes, small molecule probes, molecular beacons, optical (near IR dyes) and radioisotope labeled probes, animal PET and SPECT, immunohistochemistry, in situ hybridization, real-time PCR, Northern blotting, Western blotting, fluorescence (pyroglucose, NADH, oxidized flavoproteins), p53 and TRAIL pathway modulations to reverse therapeutic resistance, lead compound synthesis.

Clinical Impact
This team routinely generates novel bioluminescent probes and molecular beacons of small molecules able to reach multiple pathways to image changes in gene expression changes or protein-protein interactions important for cancer development and therapy. There is a strong translational drug development component. This team is complements NTROI goals with strengths that address cell biological questions fundamental to cancer biology and improvements in diagnosis, monitoring progression, predicting outcomes, and improving therapy. They study early detection of colonic neoplasms, lymphatic spread and nodal metastasis, non-invasive imaging of angiogenesis and its correlates in hypoxia, early detection of specific markers of therapeutic response, and toxicity. They have strong probe development capabilities suitable for both optical and nuclear-modality imaging.

Strengths
Cell biology, molecular pathways, gene expression, and small molecular probes and drug development. Clinical dissemination of probes likely would be beyond 5 years due to imaging drug regulatory requirements.

Synergisms with Other Teams
Provides access to probes and molecular beacons with radiolabeled versions for validations, molecular methods able to add insights into cancer biology, and studies of epithelial origin colon cancers that mesh with the epithelial origin breast and esophageal cancers of Teams 1 and 2.

University of Pennsylvania NTROI Imaging Core ¹⁰
Stanford University

Detection of Neoplasia in the Esophagus
Christopher Contag, Ph.D., Principal Investigator
ccontag@cmgm.stanford.edu ⁹
Stanford University

Grant Number: 1U54CA105296-01

Participating Organizations

• Academic: Stanford University, Palo Alto VA Hospital, Vanderbilt University, University of Florida
• Industrial: Mauna Kea Technologies, Optical Biopsy Technologies Inc

Modalities
Fluorescence and reflectance endoscopy for wide area target identification, dual-axes confocal microscopic-endoscopy for sub-cellular resolution and fluorescence detection, optical contrast agent development of fluorescent molecular probes with near IR-dye labeling, phage-display library for identifying peptides specific for neoplastic Barrett's mucosa (cell surface markers). Also cyclooxygenase-2 inhibitors with fluorescent tags for neoplastic disease and inflammation.

Clinical Impact
This team uses phage-display libraries to identify target peptides for near IR-labeled fluorescent probes. They have COX-2 agents, are identifying other cell surface markers specific for Barrett's mucosal neoplasia, and expect to be able to differentiate between high and low grade cells. They have at least one peptide that makes this distinction now. They are starting clinical evaluations to optimize designs and validate instruments and reagents. Team focus includes instrument development and extends to key issues in cancer biology with scope from oncogenesis through clinical detection. They are set up to use optical detection of molecular markers of disease, develop understanding of basic mechanisms of esophageal cancer, and apply these tools to develop effective detection strategies.

Strengths
Cell biological processes to discover molecular markers of disease, developments of labeled probes specific for them, dual-function endoscopic instrument development for stand-off fluorescence surveillance and then sub-cellular resolution by confocal microscopy of lesions in vivo. Early clinical dissemination by year 5 appears possible.

Synergisms with Other Teams
This team has a focus on esophageal epithelial dysplasias. Their technologies have evident synergisms with Team 1's ductal and lobular epithelial-origin breast cancer work, benefit from Team 2's pharmacokinetics and other in vivo analytical powers applied to Barrett's, Breast cancer, and Cervical dysplasias, and have commonality with Team 3's focus on epithelial cancers of the distal GI tract (colorectal dysplasias) and metastasis.