Nanotechnology has the potential to significantly impact the development of small animal models of cancerincluding models to test new antineoplastic therapies. In this project we will develop mouse tumor xenoqraftmodels that will allow us to test if we can combine both tissue/serum nanosensor based proteomic analysisand molecular imaging with targeted fluorescent quantum dots to predict and monitor treatment responsewith specific therapies. These models are important to the overall vision of this CCNE-TR for which wouldlike to eventually utilize ex vivo nanosensors and in vivo molecular imaging in cancer patients for improvinghow we predict and monitor response to therapies.
In Aim 1 we will optimize small animal optical imaginginstrumentation for imaging quantum dots and also work with General Electric Global Research to developand test a new frequency domain optical imaging instrument.
In Aim 2 we will utilize biologically targetedquantum dots developed in Projects 5 and 6 to image tumors in living mice. We will proceed systematicallyfrom targeting one known tumor cell surface antigen (CD20 in our lymphoma xenograft model) to targetingseveral known tumor cell surface antigens (her2/her3/PSCA in our prostate cancer model), before expandingour target range to neovascularization (avp3 Integrin) and extracellular matrix targets (Matrixmetalloproteinase 2, MMP2).
In Aim 3 we will develop mouse models of lymphoma for testing antineoplastictherapies in order to study changes in proteins at the cell membrane, in the secretome, and in serum. Cellsurface and serum proteome will be analyzed by Solid Phase Extraction of Glycoproteins (SPEC) and LiquidChromatography Mass Spectrometry (SPEG/MS), whereas secretome will be assessed by biotin captureand subsequent cellular functional profiling array for changes that are predictive of response to therapy. Wewill test two lymphoma therapy models, one xenograft model for human lymphoma mimicking response vs.resistance to Rituxan therapy, and a mouse pre-clinical model of response vs. resistance to targetedinactivation of the MYC oncogene.
In Aim 4 we will test a mouse cancer model using the results from theprevious three aims in order to determine the utility of integrating ex vivo and in vivo nanotechnologies todetermine protein changes in the tissue/serum and to image molecular changes pre and post-therapy. Thesignificance of this work is that it should help set the foundation for using ex vivo nanosensors in clinicaltrials, to allow development of novel molecular imaging probes for clinical trials, and to improve drug testingin small animal cancer models. This should lead to marked improvement in predicting and monitoringresponse to therapy in cancer patients.
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