Project Grant R43CA272030

TWO-COLOR NEAR-INFRARED FLUORESCENCE GUIDED SURGERY TOOLS ENABLING SIMULTANEOUS CANCER MARGIN AND NERVE VISUALIZATION DURING HEAD AND NECK SQUAMOUS CELL CARCINOMA RESECTION - PROJECT SUMMARY HEAD AND NECK SQUAMOUS CELL CARCINOMA (HNSCC) IS THE SIXTH HIGHEST INCIDENCE CANCER WORLDWIDE, WITH >650,000 CASES ANNUALLY. SURGERY IS A PRIMARY TREATMENT OPTION FOR HNSCC, DURING WHICH SURGEONS FACE TWO MAIN GOALS: 1) COMPLETE CANCER RESECTION AND 2) PRESERVATION OF NORMAL TISSUE STRUCTURES SUCH AS MUSCLE, BLOOD VESSELS, AND NERVES TO ENSURE POST-SURGICAL QUALITY OF LIFE. UNFORTUNATELY, THESE GOALS ARE NOT SYNERGISTIC, WHERE COMPLETE CANCER RESECTION IS OFTEN LIMITED BY EFFORTS TO PRESERVE NORMAL TISSUE AND REDUCE LIFE ALTERING COMORBIDITIES. IN FACT, POSITIVE SURGICAL MARGINS ARE FOUND IN 20-30% OF PATIENTS, AND NERVE DAMAGE REPRESENTS A MAJOR SURGICAL COMORBIDITY, WITH 5-30% OF PATIENTS EXPERIENCING LASTING PAIN OR LOSS OF FUNCTION. CURRENTLY, NO TECHNOLOGY EXISTS TO ENHANCE INTRAOPERATIVE CANCER AND NERVE RECOGNITION. THUS, TECHNOLOGY TO PROVIDE DIRECT VISUALIZATION OF CANCER MARGINS AND NERVES SIMULTANEOUSLY IN REAL TIME WOULD GREATLY IMPROVE SURGICAL OUTCOMES AND REDUCE COMORBIDITIES FOR HNSCC PATIENTS. FLUORESCENCE GUIDED SURGERY (FGS) HAS SUCCESSFULLY INTEGRATED INTO CLINICAL MEDICINE, PROVIDING SURGEONS REAL-TIME VISUALIZATION OF IMPORTANT TISSUES AND COMPLEX ANATOMY. USING COMPACT AND HIGH-RESOLUTION FGS IMAGING SYSTEMS, WHICH OPERATE ALMOST EXCLUSIVELY IN THE NEAR-INFRARED (NIR, 700-900 NM), SURGEONS CAN IMAGE TARGETED FLUORESCENT PROBES WITH HIGH CONTRAST AT UP TO CENTIMETER DEPTHS. NIR NERVE-SPECIFIC AND HNSCC-TARGETED PROBES UNDER DEVELOPMENT WOULD TOGETHER PROVIDE AN INTEGRATED FGS TOOL FOR HNSCC RESECTION. SEVERAL PEPTIDE-BASED FGS IMAGING PROBES HAVE DEMONSTRATED EFFICACY IN IDENTIFYING TUMOR MARGINS AND ARE CURRENTLY IN PHASE II AND III CLINICAL TRIALS, INCLUDING THOSE TARGETING EPIDERMAL GROWTH FACTOR RECEPTOR (EGFR), MATRIX METALLOPROTEASE (MMP), AND INTEGRINS. WE HAVE DEVELOPED FIRST-IN-CLASS NIR NERVE-SPECIFIC FLUORESCENT SMALL-MOLECULE PROBES THAT DEMONSTRATE HIGH NERVE SIGNAL TO ALL BACKGROUND TISSUES (E.G., MUSCLE, ADIPOSE, VASCULATURE, FASCIA, ETC.) FOLLOWING INTRAVENOUS ADMINISTRATION IN RODENTS AND SWINE. IMPORTANTLY, THE TUMOR-TARGETING FGS PROBES UTILIZE FLUORESCENT REPORTERS CENTERED AT 800-NM WAVELENGTHS, WHILE OUR NERVE-SPECIFIC PROBES FLUORESCE AT 700-NM WAVELENGTHS, PROVIDING SPECTRALLY DISTINCT TISSUE DETECTION AND COMPATIBILITY WITH EXISTING TWO-COLOR FGS SYSTEMS. THE COMBINATION OF THESE TWO PROMISING TECHNOLOGIES WOULD PROVIDE A COMPREHENSIVE, INNOVATIVE SOLUTION TO ENHANCE CANCER CONTROL AND NERVE SPARING DURING HNSCC RESECTION. THIS STUDY'S IMMEDIATE MILESTONES WILL INCLUDE (1) CHARACTERIZATION OF OUR LEAD NIR NERVE-SPECIFIC FLUOROPHORE FOR HEAD AND NECK PROCEDURES, (2) QUANTIFICATION OF TUMOR- AND NERVE-SPECIFIC FGS PROBE CO-ADMINISTRATION PERFORMANCE INCLUDING CROSS-TALK, AND (3) ASSESSMENT OF THIS TECHNOLOGY USING A CLINICAL TWO-COLOR FGS SYSTEM. THIS WORK WILL RESULT IN THE FIRST COMPREHENSIVE FGS TOOL FOR CANCER RESECTION AND NERVE SPARING DURING HEAD AND NECK PROCEDURES. THE PROPOSED DEVELOPMENT WILL PROVIDE IMPORTANT PROOF-OF-CONCEPT FOR FURTHER DEVELOPMENT AND PARTNERSHIP. IN PHASE II, THE FIRST TWO-COLOR TUMOR AND NERVE TARGETED FGS STUDIES WILL BE COMPLETED IN PATIENTS UNDERGOING HNSCC RESECTION.