Collagen type I PET/MRI enables evaluation of treatment response in pancreatic cancer in pre-clinical and first-in-human translational studies
Shadi A. Esfahani, Hua Ma, Shriya Krishna, Sergey Shuvaev, Mark F Sabbagh, Caitlin Deffler, Nicholas J. Rotile, Jonah Weigand‐Whittier, Iris Y. Zhou, Ciprian Catana, Onofrio A. Catalano, David T. Ting, Pedram Heidari, Eric Abston, Michael Lanuti, Genevieve M. Boland, Priyanka Pathak, Hannah Roberts, Kenneth K. Tanabe, Motaz Qadan, Carlos Fernández-del Castillo, Angela Shih, Aparna R. Parikh, Colin D. Weekes, Theodore S. Hong, Peter Caravan
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is an invasive and rapidly progressive malignancy.A major challenge in patient management is the lack of a reliable imaging tool to monitor tumor response to treatment.Tumor-associated fibrosis characterized by high type I collagen is a hallmark of PDAC, and fibrosis further increases in response to neoadjuvant chemoradiotherapy (CRT).We hypothesized that molecular positron emission tomography (PET) using a type I collagen-specific imaging probe, 68 Ga-CBP8 can detect and measure changes in tumor fibrosis in response to standard treatment in mouse models and patients with PDAC.Methods: We evaluated the specificity of 68 Ga-CBP8 PET to tumor collagen and its ability to differentiate responders from non-responders based on the dynamic changes of fibrosis in nude mouse models of human PDAC including FOLFIRNOX-sensitive (PANC-1 and PDAC6) and .Next, we demonstrated the specificity and sensitivity of 68 Ga-CBP8 to the deposited collagen in resected human PDAC and pancreas tissues.Eight male participant (49-65 y) with newly diagnosed PDAC underwent dynamic 68 Ga-CBP8 PET/MRI, and five underwent follow up 68 Ga-CBP8 PET/MRI after completing standard CRT.PET parameters were correlated with tumor collagen content and markers of response on histology.Results: 68 Ga-CBP8 showed specific binding to PDAC compared to non-binding 68 Ga-CNBP probe in two mouse models of PDAC using PET imaging and to resected human PDAC using autoradiography (P < 0.05 for all comparisons).68 Ga-CBP8 PET showed 2-fold higher tumor signal in mouse models following FOLFIRINOX treatment in PANC-1 and PDAC6 models (P < 0.01), but no significant increase after treatment in FOLFIRINOX resistant SU.86.86 model.68 Ga-CBP8 binding to resected human PDAC was significantly higher (P < 0.0001) in treated versus untreated tissue.PET/MRI of PDAC patients prior to Ivyspring International