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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA132971-05
Application #
8412975
Study Section
Special Emphasis Panel (ZRG1-SBIB-S (50))
Program Officer
Menkens, Anne E
Project Start
2009-01-01
Project End
2014-06-30
Budget Start
2013-01-01
Budget End
2014-06-30
Support Year
5
Fiscal Year
2013
Total Cost
$278,595
Indirect Cost
$51,557
Name
University of California San Diego
Department
Surgery
Type
Schools of Medicine
DUNS #
804355790
City
La Jolla
State
CA
Country
United States
Zip Code
92093
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Metildi, Cristina A; Kaushal, Sharmeela; Pu, Minya et al. (2014) Fluorescence-guided surgery with a fluorophore-conjugated antibody to carcinoembryonic antigen (CEA), that highlights the tumor, improves surgical resection and increases survival in orthotopic mouse models of human pancreatic cancer. Ann Surg Oncol 21:1405-11
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Hiroshima, Yukihiko; Maawy, Ali; Zhang, Yong et al. (2014) Fluorescence-guided surgery in combination with UVC irradiation cures metastatic human pancreatic cancer in orthotopic mouse models. PLoS One 9:e99977
Hiroshima, Yukihiko; Maawy, Ali; Metildi, Cristina A et al. (2014) Successful fluorescence-guided surgery on human colon cancer patient-derived orthotopic xenograft mouse models using a fluorophore-conjugated anti-CEA antibody and a portable imaging system. J Laparoendosc Adv Surg Tech A 24:241-7
Miwa, Shinji; Hiroshima, Yukihiko; Yano, Shuya et al. (2014) Fluorescence-guided surgery improves outcome in an orthotopic osteosarcoma nude-mouse model. J Orthop Res 32:1596-601
Yano, Shuya; Miwa, Shinji; Mii, Sumiyuki et al. (2014) Invading cancer cells are predominantly in G0/G1 resulting in chemoresistance demonstrated by real-time FUCCI imaging. Cell Cycle 13:953-60

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