Molecular Imaging Probe(s) for Optical Surgical Navigation of Pancreatic Cancer

ABSTRACT
Pancreatic cancer (PC) is an aggressive malignancy where surgical resection is the most effective curative
option. Reliance on bright light visualization and tactile cues limit the efficiency of surgical resection for PC and
its premalignant precursor lesions and contribute to unfavorable outcomes. Intraoperative fluorescence guidance
improves both stagings as well as the accuracy of oncologic surgeries and results in lower local recurrence rates
and improved survival. The success of fluorescence-guided imaging is dependent on the sensitivity and
specificity of a marker being utilized for detecting PC and its precursor lesions. Multiple studies from our
laboratory and others have established the differential expression of MUC4 in pancreatic pathologies. While it is
undetectable in the normal pancreas, de novo overexpression of MUC4 is restricted to high-risk-precursor
lesions and invasive PC and its expression increases progressively disease advancement. An in-house
generated monoclonal antibody (mAb) against MUC4, 8G7, which recognizes repetitive epitopes in the tandem
repeat domain, has emerged as a useful tool for ultrasensitive detection and defining the role of MUC4 in tumor
progression and metastasis. High MUC4 expression in PC is associated with poor survival, while in precursor
lesions, MUC4 expression is a predictor of malignant risk. Our preliminary studies indicate that systemically
administered mAb 8G7 labeled with NIRF dye IRDye800CW can very sensitively illuminate MUC4-expressing
subcutaneous and orthotopic tumors in vivo. Further, we have developed a unique animal model that
recapitulates MUC4-driven IPMN-to-invasive PC progression. In this model, pancreas-specific inducible
expression of human MUC4 in conjunction with oncogenic KrasG12D results in the development of premalignant
IPMN and PanIN lesions that progress to invasive PC. The proposal seeks to develop and evaluate MUC4-
targeted NIR probes for optical surgical navigation of PC and its premalignant precursor lesions in the preclinical
models. We hypothesize that intraoperative use of MUC4-targeted Near-Infrared Fluorescent (NIRF)
imaging probes will improve the resection of PC and its high-risk precursor lesions. To test this
hypothesis, two specific aims are proposed. Studies in Aim 1 focus on the synthesis, characterization, and (pre)
clinical safety profiling of MUC4-targeted near-infrared fluorescent conjugates. Aim 2 studies evaluate the
preclinical efficacy of MUC4-targeted imaging probes in patient-derived orthotopic xenograft (PDOX) models,
human MUC4 transgenic GEM models, and clinical specimens. Overall, the development of targeted imaging
probes can improve both the detection and margin-free resection of precursor lesions and PC. The studies
proposed in this application will develop and test high-performance NIR probes targeting MUC4 (a top
differentially overexpressed membrane mucin in PC) for surgical navigation in PC and its precursor lesions.
Successful accomplishment of study goals will pave the path for a Phase I clinical trial for urgently needed
imaging probes for improved detection and surgical resection of PC and its high-risk precursor lesions.

Grant Number: 5R01CA256973-04
NIH Institute/Center: NIH
Principal Investigator: Michael Bouvet