The lack of biomarkers for assessment of which patients may respond to pathway-targeted therapy creates a? profound need for the application of integrated technologies for the discovery and translational validation of? such biomarkers. Recent advances in proteomic methods and computational bioinformatics processing have? enabled application of integrated proteomic technologies to the discovery of biomarkers. If used by ex vivo? nano-sensor devices and in vivo nanoparticle imaging methods such biomarkers may provide effective new? tools to cancer therapy development and use. We propose to discover candidate markers by integrating two? directed and two comprehensive proteomic technologies: a) intracellular-signaling protein chips consisting of? a directed analysis method which quantitates known, intracellular signaling proteins; b) living-cell capture? sensor arrays which represent a nanosensor approach for directed analysis of the cell-surface and secretory? proteomes; c) biotin-capture-based cell-surface profiling methods consisting of a comprehensive analysis? method that identifies and quantitates the abundance of cell-surface proteins; d) solid-phase extraction of? glycoprotein (SPEG) profiling, which is a comprehensive analysis method for the study of secreted proteins? and blood. Biomarker discovery will initially be disease- (prostate cancer) and pathway- (human epidermal? growth factor receptor (Her)-kinase axis) focused and will provide a foundation our CCNE-TR Center will use? to produce, evaluate and validate nanosensors and nanoparticle-based imaging. We will first define the cell-surface? and secretory proteomes of androgen-independent prostate cancer and identify proteins within these? and the intracellular proteome that are indicative of the perturbations to the Her-kinase axis. We will analyze? these sub-proteomes in primary culture models of androgen-independent prostate cancer by treatment with? the Her-kinase targeted therapeutics, 2C4 (a humanized monoclonal antibody that binds epitopes on Her-2? that prevent ligand-mediated Her-2 heterodimerization) and geftinib (a small molecule inhibitor that competes? for the ATP binding site on epidermal growth factor receptor). We will additionally stimulate with ligands? targeting each of the receptor-dimer partners of this axis. Axis-response-informative proteins will be? evaluated for their Her-kinase and prostate cancer specificity, by comparison with a database of gene and? protein expression in other cell lines of different tissue origin available to the investigator group. Next we will? integrate our in vitro results with information of the protein expression patterns of human xenograft models to? identify a panel of markers with utility for predicting and/or for monitoring response. The bank of blood and? viable tissue samples developed by the UCLA Prostate SPORE for use in this project represent different pre? and post-treatment time points and a diverse collection of androgen-independent xenograft models? characterized for sensitivity to the Her-kinase-targeted therapeutics. Lastly we will validate the utility of the? biomarkers discovered in Specific Aims 1 and 2 for use with ex vivo nanosensor devices and in vivo? nanoparticle imaging by generating affinity reagents for protein candidates; We will also validate the panel's? ability to guiding human therapeutic intervention by using SPORE tissue and serum samples of prostate? cancer patients treated with Her-kinase-directed therapies.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Specialized Center--Cooperative Agreements (U54)
Project #
Application #
Study Section
Special Emphasis Panel (ZCA1)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Stanford University
United States
Zip Code
Shah, Preyas N; Lin, Tiras Y; Aanei, Ioana L et al. (2018) Extravasation of Brownian Spheroidal Nanoparticles through Vascular Pores. Biophys J 115:1103-1115
Kani, Kian; Garri, Carolina; Tiemann, Katrin et al. (2017) JUN-Mediated Downregulation of EGFR Signaling Is Associated with Resistance to Gefitinib in EGFR-mutant NSCLC Cell Lines. Mol Cancer Ther 16:1645-1657
Antaris, Alexander L; Chen, Hao; Diao, Shuo et al. (2017) A high quantum yield molecule-protein complex fluorophore for near-infrared II imaging. Nat Commun 8:15269
Smith, Bryan Ronain; Gambhir, Sanjiv Sam (2017) Nanomaterials for In Vivo Imaging. Chem Rev 117:901-986
Shou, Kangquan; Qu, Chunrong; Sun, Yao et al. (2017) Multifunctional biomedical imaging in physiological and pathological conditions using a NIR-II probe. Adv Funct Mater 27:
Feng, Yi; Zhu, Shoujun; Antaris, Alexander L et al. (2017) Live imaging of follicle stimulating hormone receptors in gonads and bones using near infrared II fluorophore. Chem Sci 8:3703-3711
Willmann, J├╝rgen K; Bonomo, Lorenzo; Carla Testa, Antonia et al. (2017) Ultrasound Molecular Imaging With BR55 in Patients With Breast and Ovarian Lesions: First-in-Human Results. J Clin Oncol 35:2133-2140
Antaris, Alexander L; Chen, Hao; Cheng, Kai et al. (2016) A small-molecule dye for NIR-II imaging. Nat Mater 15:235-42
Pu, Kanyi; Chattopadhyay, Niladri; Rao, Jianghong (2016) Recent advances of semiconducting polymer nanoparticles in in vivo molecular imaging. J Control Release 240:312-322
Zhang, Ruiping; Cheng, Kai; Antaris, Alexander L et al. (2016) Hybrid anisotropic nanostructures for dual-modal cancer imaging and image-guided chemo-thermo therapies. Biomaterials 103:265-277

Showing the most recent 10 out of 228 publications