We propose to develop novel ErbB-targeted probes and assays to provide clinically applicable assessments of ErbB receptor function. in the setting of ErbB-targeted therapies. These tools include molecular probes using phage antibody-based technologies, cellular assay using micrometastasis detection technologies, and Imaging evaluations using MRI. and SPECT/PET -based technologies. Together, these are designed to provide powerful and complementary analyses of ErbB function, such as ErbB expression levels; interactions among ErbB members; receptor phosphorylation, signaling, internalization, and down modulation; ErbB biodistribution; and interactions with therapeutic ligands. These tools will be used in conjunction with new ErbB-targeted therapies, which encompass an important and expanding group of therapeutic strategies and agents. For example, ErbB2 (HER2, neu) has become a paradigm for targeted therapies, due to proof-of-concept with anti-ErbB2 MAb (trastuzumab/Herceptin); yet, the mechanism of action, resistance mechanisms, and predictive factors for this agent are poorly understood and controversial, and assessments of the """"""""model"""""""" antigen ErbB2 have turned out to be glaringly incomplete with existing methodologies. Our novel ErbB functional assessments will be used in preclinical and clinical studies to better understand the biological and mechanistic effects of various ErbB-targeted therapies, to monitor these effects over time, to predict response/resistance associated with treatment, and to provide validation and optimization of novel therapies. Our tools will facilitate early, mechanism-based assessments of these therapies. Our interdisciplinary molecular target assessment team consists of closely integrated projects and cores: Project 1, Detection, ErbB Characterization. and Molecular Profiling of Micrometastases to Assess ErbB- Targeted Agents (J, Park) Project2. Novel Phage Antibody-Based Probes of ErbB Function (J. Marks) . Project 3. Non-Invasive Imaging of ErbB Receptor-Ligand Interactions by Novel MRI and SPECT/PET Strategies (N. Hylton and H. VanBrocklin). Dev. Project 1, Development of Expression Array Analysis of ErbB-receptor Targeted Therapies (D. Tripathy). Dev. Project 2. PET -Based Assessments of Apoptosis (S. Taylor). Administrative Core (M. Tempero). Immunopathology Core (A. Thor). Pharmacology Core (D. Kirpotin). Given the prominent role of ErbB receptors in many cancer types and the many novel agents under active development to target these cancers, our ErbB-targeted assessments will have potentially wide applicability in cancer treatment. Also, the evaluation strategies to be developed here will serve as a model for the functional assessment of cell surface receptor-tyrosine kinases generally. Collaborating Institutions: Northwestern University; California Pacific Medical Center Research Institute; Lawrence Berkeley National Lab
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