Fluorescence guided nerve sparing during colorectal cancer surgery using local application of a near infrared nerve fluorophore - PROJECT SUMMARY Colorectal cancer (CRC) is the second leading cause of cancer death and is predicted to cause nearly 10% of cancer deaths worldwide in 2024. Rectal cancer (RC) accounts for more than one-third of CRC cases, where surgical resection is a standard primary treatment. However, surgeons must balance two main goals: RC cure and nerve preservation to prevent both mortality and lifelong morbidity, respectively. With little visual acuity for nerve plexus recognition and conclusive cancer delineation, ideal outcomes for patients continue to challenge even experienced surgeons. Positive surgical margins and nerve damage occur in up to 8 and 30% of patients, respectively, resulting in poor cancer control as well as incontinence and sexual dysfunction, severely affecting post-operative quality of life. No clinically approved methods exist to enhance direct RC or nerve plexus visualization intraoperatively, where improved delineation of either tissue could substantially improve surgical outcomes. Herein, we will address this unmet clinical need by enabling real-time nerve visualization. Fluorescence-guided surgery (FGS) has demonstrated clinical efficacy in improving surgical outcomes for cancer patients through the use of tumor-specific, molecularly targeted fluorescent contrast agents in conjunction with clinically approved imaging systems. FGS systems operate almost exclusively in the near-infrared (NIR, 650- 900 nm) region, where tissue chromophore absorbance, autofluorescence and scatter all fall to local minima, allowing high contrast imaging at up to centimeter depths. However, to date, there are no clinically approved nerve-specific fluorescent contrast agents with an emission profile compatible with current NIR FGS systems. In preliminary work, our team has developed a library of >400 novel oxazine-based small molecule fluorophores with excitation and emission wavelengths spanning the NIR region. This library enabled identification of the first nerve-specific contrast agent, LGW08-35, with an emission wavelength compatible with current NIR FGS systems that are designed to image FDA-approved indocyanine green (ICG). To enable clinical translation for intraoperative use, we have also developed a clinically relevant formulation for LGW08-35 that can be directly/topically applied as a liquid and rapidly gels upon tissue contact. Hydrogel-formulated LGW08-35 permits nerve-trajectory mapping within minutes of low-dose LGW08-35 application, providing surgeons with new intraoperative on-the-spot decision-making opportunities during crucial moments of the procedure when patients are at high risk of poor postoperative outcomes due to unexpected challenges with delineation between cancer and nerve tissues. In this proposed study, Drs. Gibbs and Alani (MPI) will utilize their complementary expertise in nerve contrast agent development and clinically relevant formulation strategies, respectively, in partnership with Dr. Vahrmeijer, who has complementary expertise in FGS trials. Our team is poised to translate a clinically relevant NIR nerve imaging solution to first in human (FIH) clinical trials. Herein, we will develop GMP-compliant LGW08-35 drug product and complete GLP-grade pharmacology and toxicology testing and FIH Phase I trials.
