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 the use of fluorophore-conjugated antibodies for surgical navigation and laparoscopic localization of gastrointestinal tumors. The proposed research will develop advanced imaging technology, methods and tools for mouse-model studies that will be translatable to the clinic to develop fluorescence-guided cancer surgery. Hypothesis Fluorophore-labeled antibodies against tumor-specific antigens will improve visualization, detection, and resection of primary and metastatic pancreatic and colon cancer.
Specific Aim 1 Utilization of fluorophore-labeled monoclonal antibody specific for the tumor antigen CA19-9, CEA, or a combination of both to facilitate imaging and resection of tumor margins and metastatic lesions in pancreatic and colon cancer. We will use fluorescent-conjugated monoclonal antibodies against tumor antigen CA19-9 and CEA or a combination of both to evaluate tumor burden in vivo in an orthotopic metastatic nude mouse model of human pancreatic and colon cancer and to facilitate the complete resection of orthotopic and metastatic lesions. Toxicity, dosing, and tissue distribution studies will be performed for fluorophore-conjugated monoclonal antibodies.
Specific Aim 2 We will compare several different fluorophores for in vivo dosing response, in vivo signal duration, in vivo photobleaching, and in vivo signal-to-background ratio in our mouse models of human pancreatic cancer. Fluorophores can vary greatly in their in vivo intensity of initial fluorescence emission, duration of fluorescence signal, scatter and absorption by overlying tissues and propensity for loss of fluorescence intensity with prolonged exposure to bright light, a phenomenon known as photobleaching. Due to these differences between fluorophores, it is of vital importance to choose a stable fluorophore with appropriate wavelength and signal intensity for in vivo use. We will examine several different fluorophores in the green (480-520 nm), yellow (550-570 nm), red (610-650 nm), and far-red (680-710 nm) ranges in our orthotopic metastastic nude mouse models of human pancreatic cancer to determine the optimal fluorophore candidates for potential clinical use for fluorescence guided cancer surgery in humans.
Specific Aim 3 Utilization of fluorescence laparoscopy to improve visualization of primary and metastatic GI cancers not otherwise seen under normal laparoscopic lighting. The ability to clearly distinguish all fluorescently-labeled cancerous tissue pre-operatively via laparoscopy can eliminate the morbidity from an unnecessary laparotomy and direct subsequent treatment of pancreatic and colon cancer. We will use the optimal combination of antibodies and fluorophores as determined by the aims listed above to compare the extent of tumor detection during laparoscopy under fluorescence versus traditional laparoscopy.

Public Health Relevance

Colorectal and pancreatic cancers together comprise the third and fourth most common causes of cancer- related death in the United States. For both diseases the complete detection of primary and metastatic tumor is critical to patient outcomes. Our goal is to utilize the growing technology of fluorescence imaging to both develop new methods of intraoperative staging for colorectal and pancreatic cancer and to improve our ability to achieve true resection at the time of surgery.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA142669-05
Application #
8657859
Study Section
Special Emphasis Panel (ZRG1-SBIB-U (50))
Program Officer
Nordstrom, Robert J
Project Start
2010-06-24
Project End
2015-04-30
Budget Start
2014-05-01
Budget End
2015-04-30
Support Year
5
Fiscal Year
2014
Total Cost
$300,912
Indirect Cost
$66,628
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
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
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
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
Park, Jeong Youp; Lee, Jin Young; Zhang, Yong et al. (2016) Targeting the insulin growth factor-1 receptor with fluorescent antibodies enables high resolution imaging of human pancreatic cancer in orthotopic mouse models. Oncotarget 7:18262-8
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
Hoffman, Robert M (2015) Application of GFP imaging in cancer. Lab Invest 95:432-52
Hiroshima, Yukihiko; Maawy, Ali; Zhang, Yong et al. (2015) Fluorescence-guided surgery, but not bright-light surgery, prevents local recurrence in a pancreatic cancer patient derived orthotopic xenograft (PDOX) model resistant to neoadjuvant chemotherapy (NAC). Pancreatology 15:295-301
Park, Jeong Youp; Hiroshima, Yukihiko; Lee, Jin Young et al. (2015) MUC1 selectively targets human pancreatic cancer in orthotopic nude mouse models. PLoS One 10:e0122100
Hiroshima, Yukihiko; Maawy, Ali A; Katz, Matthew H G et al. (2015) Selective efficacy of zoledronic acid on metastasis in a patient-derived orthotopic xenograph (PDOX) nude-mouse model of human pancreatic cancer. J Surg Oncol 111:311-5
Hiroshima, Yukihiko; Zhang, Yong; Zhao, Ming et al. (2015) Tumor-Targeting Salmonella typhimurium A1-R in Combination with Trastuzumab Eradicates HER-2-Positive Cervical Cancer Cells in Patient-Derived Mouse Models. PLoS One 10:e0120358

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