We propose a unique academic-industrial partnership between investigators at UCSD (Academic Partner) and AntiCancer (Industrial Partner) to develop and validate color-coded fluorescent imaging systems in mouse models of pancreatic cancer. The proposed research will facilitate advanced imaging technology, methods and tools for mouse-model studies. Findings from these studies will advance our knowledge of tumor- host interactions in pancreatic cancer and will lead to novel treatments for this almost uniformly fatal disease. Hypothesis Color-coded fluorescence imaging can distinguish pancreatic cancer cells from host angiogenic vessels and stromal cells and will be useful for evaluating selective anti-stromal agents.
Specific Aim 1 (Years 1-3) Development of color-coded imageable models of the pancreatic cancer microenvironment. We have developed a simple yet powerful new model for delineating the morphological events of tumor-induced angiogenesis using dual color fluorescence imaging. The host model is ND-GFP transgenic nude mouse, developed in our laboratory, in which nascent blood vessels are labeled with GFP and tumors are labeled with red fluorescent protein (RFP). We plan to color-code the tumor microenvironment of this model with stromal cells (macrophages, lymphocytes, dendritic, and bone marrow cells) harvested from ubiquitously-expressing GFP, RFP, CFP (blue) and GFP-RFP (yellow) transgenic immunocompetent mice.
Specific Aim 2 (Years 2-4) Development of a model system allowing real-time in-vivo imaging of murine lymphatics and intralymphatic cancer cell trafficking to facilitate the study of lymph node targeting by metastatic tumor cells. We are developing a model system allowing real-time in-vivo imaging of murine lymphatics and intralymphatic cancer cell trafficking to facilitate the study of lymph node targeting by metastatic tumor cells. The model utilizes RFP-labeled human pancreatic cancer cells and monoclonal anti-LYVE1 antibody to label lymphatic vessels in order to image lymphatic trafficking of tumor cells. Cells delivered to the lymphatic system are recorded on video in real-time leaving the inguinal lymph node and entering the axillary lymph node. The use of fluorescent LYVE-1 allows detailed imaging of tumor cell interaction with lymphatic vessel walls and valves, facilitating observation of the dynamics of intralymphatic cellular trafficking.
Specific Aim 3 (Years 3-5) Determination of the efficacy of novel anti-stromal therapies for pancreatic cancer in our color-coded fluorescent in vivo orthotopic and lymphatic mouse models. Several novel anti-stromal, anti-angiogenic, and anti-lymphangiogenic agents including monoclonal antibodies against integrins and small molecule inhibitors of angiogenesis will be tested for their efficacy in the novel color-coded pancreatic cancer microenvironment models developed in specific aims 1 and 2. These color-coded nude mouse models of human pancreatic cancer will be used to visualize new targets that should greatly enhance the discovery of anti-stromal, anti-angiogenic and anti-lymphangiogenic drugs for pancreatic cancer.
Pancreatic cancer is a fatal disease with 5-year survival rates of only 1-4%. Clearly, new treatment strategies are needed. We propose a unique academic industrial partnership between investigators at the University of California San Diego (Academic Partner) and AntiCancer, Inc. (Industrial Partner) to develop and validate color-coded fluorescent imaging system in mouse models of pancreatic cancer that can be used for evaluation of new drugs.
|Hwang, Ho Kyoung; Murakami, Takashi; Kiyuna, Tasuku et al. (2017) Splenectomy is associated with an aggressive tumor growth pattern and altered host immunity in an orthotopic syngeneic murine pancreatic cancer model. Oncotarget 8:88827-88834|
|DeLong, Jonathan C; Murakami, Takashi; Yazaki, Paul J et al. (2017) Near-infrared-conjugated humanized anti-carcinoembryonic antigen antibody targets colon cancer in an orthotopic nude-mouse model. J Surg Res 218:139-143|
|Strnadel, Jan; Choi, Sunkyu; Fujimura, Ken et al. (2017) eIF5A-PEAK1 Signaling Regulates YAP1/TAZ Protein Expression and Pancreatic Cancer Cell Growth. Cancer Res 77:1997-2007|
|Yano, Shuya; Takehara, Kiyoto; Kishimoto, Hiroyuki et al. (2016) Adenoviral targeting of malignant melanoma for fluorescence-guided surgery prevents recurrence in orthotopic nude-mouse models. Oncotarget 7:18558-72|
|Park, Jeong Youp; Murakami, Takashi; Lee, Jin Young et al. (2016) Fluorescent-Antibody Targeting of Insulin-Like Growth Factor-1 Receptor Visualizes Metastatic Human Colon Cancer in Orthotopic Mouse Models. PLoS One 11:e0146504|
|DeLong, Jonathan C; Hoffman, Robert M; Bouvet, Michael (2016) Current status and future perspectives of fluorescence-guided surgery for cancer. Expert Rev Anticancer Ther 16:71-81|
|Yano, Shuya; Takehara, Kiyoto; Miwa, Shinji et al. (2016) Improved Resection and Outcome of Colon-Cancer Liver Metastasis with Fluorescence-Guided Surgery Using In Situ GFP Labeling with a Telomerase-Dependent Adenovirus in an Orthotopic Mouse Model. PLoS One 11:e0148760|
|Yano, Shuya; Takehara, Kiyoto; Kishimoto, Hiroyuki et al. (2016) Tumor-targeting adenovirus OBP-401 inhibits primary and metastatic tumor growth of triple-negative breast cancer in orthotopic nude-mouse models. Oncotarget 7:85273-85282|
|Kaneda, Megan M; Cappello, Paola; Nguyen, Abraham V et al. (2016) Macrophage PI3K? Drives Pancreatic Ductal Adenocarcinoma Progression. Cancer Discov 6:870-85|
|Hiroshima, Yukihiko; Lwin, Thinzar M; Murakami, Takashi et al. (2016) Effective fluorescence-guided surgery of liver metastasis using a fluorescent anti-CEA antibody. J Surg Oncol 114:951-958|
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