Section 5 Primary ProjectA.
Specific Aims Although lymph nodal status is recognized as the single most important prognostic factor for the majority ofcancer patients, a paucity of techniques are available to diagnostically image the lymphatic vascularcompartment to assess disease status. Current practices require surgery for removal of LNs and pathology toassess disease status. Yet LN 'sampling' to avoid resection of entire nodal basins and the lack of routinecomprehensive molecular pathologies of resected tissues can result in under-staging and under-treatment ofpatients in many cancers. In this NTR program, we focus on developing optical/nuclear molecular imagingtechniques in Phase I clinical studies of nodal staging that will have an impact in three distinct clinical arenas:nuclear medicine, surgery, and molecular pathology. The ability to couple molecular imaging to currentsurgical practices of LN staging enables a unique opportunity to evaluate the accuracy and limits of detectionthrough correlation of in vivo imaging results to comprehensive molecular pathology of resected tissues.Molecular pathology will provide metrics for validation of the molecular specificity of imaging agents whereasnuclear imaging will provide validation of non-invasive optical imaging and tomography.Specifically this NTR program will focus upon the translation of dual-labeled imaging agents that willspecifically target two aspects of LN disease: (i) cancer cells within the lymphatic space and (ii) reorganizationof the stromal LN compartment as a hallmark of tumor malignancy. Agents will be translated for LN diagnosesin melanoma as well as breast cancer. The chronologically-organized specific aims of the primary project are:1. Conduct safety and toxicity studies towards the translation of SPECT/CT/Optical and PET/CT/Opticalimaging agents 111ln-DTPA-K(IRDye 800CW)-c(KRGDf) and ''Cu-DCTA-KORDye 800CW)-c(KRGDf)to assess angiogenesis involved in LN disease (Sevick, Wang, and Marshall).2. Conduct a Phase I investigational study in a melanoma patient population at the MEDVAMC withoptical imaging and tomography designed for translation under Specific Task Projects within:a. The nuclear medicine suite for multi-modality imaging of LN disease at the time of SLNB and, whennecessary, at the time of complete lymph node dissection (Berger, Bhargava, and Sevick).b. The operating room to provide surgical guidance or resection of diseased LNs and sparing ofcancer-free LNs (Berger and Sevick-Muraca).c. The molecular pathology laboratory for validation of agent targeting against immunohistochemicalstaining with S-100 (Ittman).3. Conduct safety and toxicity studies to translate SPECT/CT/Optical and PET/CT/Optical imaging agentstargeting epithelial cancer cells within the lymphatic space using a fully humanized antibody againstEpCAM labeled with 111ln-DTPA or ^Cu-DOTA and IRDye 800CW (Sevick-Muraca and Marshall).4. Conduct an exploratory Phase I investigational study in a unique population of advanced breast cancerpatients at BTGH with optical imaging and tomography for translation under Specific Task Projects in:a. The nuclear medicine suite for multi-modality imaging of LN disease at the time of 'standard-ofcare'complete lymph node dissection (Chang and Wendt).b. The operating room to assess if surgical guidance can be used to reduce the level of dissection instandard of care and surgical morbidity that may occur (see paragraph on lymphedema) (Bonefas).c. The molecular pathology laboratory to validate agent targeting with sufficient statistical power todetermine positive predictive power from concordance between imaging agent deposition inresected LNs and immunohistochemical staining for anti-cytokeratin to detect epithelial cells withinthe lymphatic space (Guiterrez, Ittman, and Hilsenbeck).Because 90% of all cancers are epithelial in origin, development of a diagnostics nuclear/optical imagingagent that targets molecular pathology's staining of a target of the epithelial cell compartment in thelymphatic space has additional targets beyond breast cancer.5. In keeping with the objectives of the NTR, we will at the discretion of the Executive Steering Committeeand with proper institutional assurances, translate one of the imaging agents developed by consortiumPis in their Project Specific Tasks or one developed by Dr. Wei Wang in the Chemistry Core.Depending upon the identified patient population and agent selected, we will engage in an exploratoryPhase I study, or extend the above exploratory studies into Phase l/ll in breast (Bonefas), melanoma(Berger and Orengo), colon (Berger), bladder (Lerner), prostate (Mims and Ittman), etc. as furtherdetailed in the application.This application is responsive to the RFA-08-002 in that it does not involve demonstration of feasibility inphantom or small animals, but rather seeks to translate developed agents, instruments, and algorithms alreadydemonstrated in humans and small animals, into the clinical problem of TNM staging.
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