Section 5 Primary Project A.
Specific Aims Although lymph nodal status is recognized as the single most important prognostic factor for the majority of cancer patients, a paucity of techniques are available to diagnostically image the lymphatic vascular compartment to assess disease status. Current practices require surgery for removal of LNs and pathology to assess disease status. Yet LN """"""""sampling"""""""" to avoid resection of entire nodal basins and the lack of routine comprehensive molecular pathologies of resected tissues can result in under-staging and under-treatment of patients in many cancers. In this NTR program, we focus on developing optical/nuclear molecular imaging techniques 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 current surgical practices of LN staging enables a unique opportunity to evaluate the accuracy and limits of detection through 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 whereas nuclear 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 will specifically target two aspects of LN disease: (i) cancer cells within the lymphatic space and (ii) reorganization of the stromal LN compartment as a hallmark of tumor malignancy. Agents will be translated for LN diagnoses in 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/Optical imaging 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 with optical 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, when necessary, 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 of cancer-free LNs (Berger and Sevick-Muraca). c. The molecular pathology laboratory for validation of agent targeting against immunohistochemical staining with S-100 (Ittman). 3. Conduct safety and toxicity studies to translate SPECT/CT/Optical and PET/CT/Optical imaging agents targeting epithelial cancer cells within the lymphatic space using a fully humanized antibody against EpCAM 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 cancer patients 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 in standard 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 to determine positive predictive power from concordance between imaging agent deposition in resected LNs and immunohistochemical staining for anti-cytokeratin to detect epithelial cells within the lymphatic space (Guiterrez, Ittman, and Hilsenbeck). Because 90% of all cancers are epithelial in origin, development of a diagnostics nuclear/optical imaging agent that targets molecular pathology's staining of a target of the epithelial cell compartment in the lymphatic 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 Committee and with proper institutional assurances, translate one of the imaging agents developed by consortium Pis 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 exploratory Phase 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 further detailed in the application. This application is responsive to the RFA-08-002 in that it does not involve demonstration of feasibility in phantom or small animals, but rather seeks to translate developed agents, instruments, and algorithms already demonstrated in humans and small animals, into the clinical problem of TNM staging.
Showing the most recent 10 out of 39 publications
