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.
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.
|Maawy, Ali A; Hiroshima, Yukihiko; Zhang, Yong et al. (2014) Polyethylene glycol (PEG) linked to near infrared (NIR) dyes conjugated to chimeric anti-carcinoembryonic antigen (CEA) antibody enhances imaging of liver metastases in a nude-mouse model of human colon cancer. PLoS One 9:e97965|
|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|
|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|
|Metildi, Cristina A; Kaushal, Sharmeela; Luiken, George A et al. (2014) Fluorescently labeled chimeric anti-CEA antibody improves detection and resection of human colon cancer in a patient-derived orthotopic xenograft (PDOX) nude mouse model. J Surg Oncol 109:451-8|
|Hiroshima, Yukihiko; Maawy, Ali; Sato, Sho et al. (2014) Hand-held high-resolution fluorescence imaging system for fluorescence-guided surgery of patient and cell-line pancreatic tumors growing orthotopically in nude mice. J Surg Res 187:510-7|
|Metildi, Cristina A; Kaushal, Sharmeela; Luiken, George A et al. (2014) Advantages of fluorescence-guided laparoscopic surgery of pancreatic cancer labeled with fluorescent anti-carcinoembryonic antigen antibodies in an orthotopic mouse model. J Am Coll Surg 219:132-41|
|Maawy, Ali A; Hiroshima, Yukihiko; Zhang, Yong et al. (2014) Specific tumor labeling enhanced by polyethylene glycol linkage of near infrared dyes conjugated to a chimeric anti-carcinoembryonic antigen antibody in a nude mouse model of human pancreatic cancer. J Biomed Opt 19:101504|
|Miwa, Shinji; Matsumoto, Yasunori; Hiroshima, Yukihiko et al. (2014) Fluorescence-guided surgery of prostate cancer bone metastasis. J Surg Res 192:124-33|
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