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.
|Lwin, Thinzar M; Hoffman, Robert M; Bouvet, Michael (2018) Advantages of patient-derived orthotopic mouse models and genetic reporters for developing fluorescence-guided surgery. J Surg Oncol 118:253-264|
|Lwin, Thinzar M; Bouvet, Michael (2018) ASO Author Reflections: Fluorescent Anti-CEA IR800 for Tumor Labeling. Ann Surg Oncol :|
|Lwin, Thinzar M; Murakami, Takashi; Miyake, Kentaro et al. (2018) Tumor-Specific Labeling of Pancreatic Cancer Using a Humanized Anti-CEA Antibody Conjugated to a Near-Infrared Fluorophore. Ann Surg Oncol 25:1079-1085|
|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|
|Murakami, Takashi; Murata, Takuya; Kawaguchi, Kei et al. (2017) Cervical Cancer Patient-Derived Orthotopic Xenograft (PDOX) Is Sensitive to Cisplatinum and Resistant to Nab-paclitaxel. Anticancer Res 37:61-65|
|Lwin, Thinzar M; Hoffman, Robert M; Bouvet, Michael (2017) Regarding the applications of fusion-fluorescence imaging using indocyanine green in laparoscopic hepatectomy. Transl Gastroenterol Hepatol 2:70|
|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|
|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|
|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|
|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|
Showing the most recent 10 out of 62 publications