The ability of the surgeon to accurately visualize tumor margins and identify metastases is necessary for the success of any cancer operation. Fluorescence imaging, because of its high sensitivity, low cost, portability, and real-time capabilities has great potential to improve surgical outcomes. Our laboratories have pioneered the use of fluorophore-conjugated tumor-specific antibodies for detection and resection of GI cancers in orthotopic mouse models with highly improved outcomes. Thus far, the fluorophores that we have utilized have been in the visible range of light. There are numerous advantages to near infrared (NIR) fluorophores which have better tissue depth of penetration compared to fluorophores in the visible range. Furthermore, we now have humanized tumor-specific anti-CEA and anti-CA 19-9 antibodies that can be used for future clinical trials. The present grant application proposes to develop the potential of using humanized anti-CEA and anti-CA 19-9 antibodies conjugated with appropriate fluorophores in the NIR 700 to 800 nm range to label primary tumors and their metastases for fluorescence laparoscopic staging, fluorescence-guided surgery (FGS), and adjuvant photoimmunotherapy of pancreatic and colon cancer in patient-derived orthotopic xenograft (PDOX) models.
The specific aims of this grant are: 1) Validation of NIR fluorophore-labeled tumor-specific humanized anti-CEA and anti-CA 19-9 antibodies to label primary tumors and metastases in PDOX mouse models of pancreatic and colorectal cancer, 2) Comparison of near infrared fluorophores conjugated to humanized anti-CEA and anti-CA 19-9 antibodies with different properties for dosing response, signal duration, photobleaching, signal-to- background ratio, and phototoxicity, in PDOX models of human pancreatic and colon cancer, 3) Development of intraoperative photoimmunotherapy (PIT) using the humanized anti-CEA and anti-CA 19-9 antibodies, or other antibodies shown to be effective in Aims 1 and 2, conjugated to IRDye 700DX as adjuvant treatment to FGS for pancreatic and colorectal cancer in PDOX nude and NSG-humanized mouse models. The completion of these aims will set the stage for clinical trials of fluorescent-antibody-based FGS that can change the paradigm of surgical oncology and greatly improve outcomes of recalcitrant cancers. Grant application features: ? Humanized tumor specific monoclonal antibodies ? Very bright tissue penetration near infrared dyes ? PDOX mouse models targeting recalcitrant pancreatic and colorectal cancer ? Fluorescence guided surgery ? Adjuvant photoimmunotherapy
In the present proposal, we will develop clinically-translatable tumor-specific near-infrared fluorescence labeling of primary and metastatic pancreatic and colorectal cancer using novel patient-derived orthotopic xenograft (PDOX) nude and humanized mouse models. We will validate humanized tumor specific anti-CEA and anti-CA 19-9 antibodies for their ability to label tumors. We will evaluate long wavelength dyes that have increased depth of penetration and ability to detect the smallest tumor deposits and provide the highest tumor to background ratios and specificity compared to dyes in the visible range. We will utilize near infrared fluorescence-guided surgery (FGS) combined with adjuvant photoimmunotherapy as a means to improve surgical outcomes for gastrointestinal cancers in PDOX humanized NSG mouse models. The completion of these aims will set the stage for clinical trials of fluorescent-antibody based FGS that can change the paradigm of surgical oncology and greatly improve outcomes of recalcitrant cancers.
|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; Hoffman, Robert M; Bouvet, Michael (2018) The development of fluorescence guided surgery for pancreatic cancer: from bench to clinic. Expert Rev Anticancer Ther 18:651-662|
|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; Kang, Chang Moo; Lee, Sung Hwan et al. (2018) Fluorescence-guided Surgery with Splenic Preservation Prevents Tumor Recurrence in an Orthotopic Nude-mouse Model of Human Pancreatic Cancer. Anticancer Res 38:665-670|