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.
Public Health Relevance Statement: PROJECT NARRATIVE Surgery is a primary treatment option for head and neck cancer patients, however, incomplete tumor resection and nerve damage plague surgical outcomes, reducing cancer-free survival rates and causing lasting pain and loss of function. Currently, no clinically approved technology exists to enhance intraoperative cancer or nerve recognition and surgeons rely solely on white light visualization and palpation. The proposed aims will develop a combination of robust peptide-based tumor-targeted fluorescent probes and novel nerve-specific fluorophores that provide enhanced direct visualization of tumor margins and nerves to enhance cancer control and nerve sparing during head and neck cancer resection.
Project Terms: Fatty Tissue; adipose; white adipose tissue; yellow adipose tissue; Adipose tissue; Anatomic Sites; Anatomic structures; Anatomy; Biological Sciences; Biologic Sciences; Bioscience; Life Sciences; Blood Vessels; vascular; Malignant Neoplasms; Cancers; Malignant Tumor; malignancy; neoplasm/cancer; Clinical Medicine; Clinical Medical Sciences; Clinical Trials; Color; comorbidity; co-morbid; co-morbidity; Contrast Media; Contrast Agent; Contrast Drugs; Radiopaque Media; intravenous administration; Face; faces; facial; Fascia; Fluorescence; Fluorescent Probes; Goals; Incidence; Integrins; Integrins Extracellular Matrix; Lead; Pb element; heavy metal Pb; heavy metal lead; Light; Photoradiation; Metalloproteases; Metallopeptidases; Metalloproteinases; Muscle; Muscle Tissue; muscular; Nerve; Palpation; Patients; Peptides; Pharmacology; Structure of phrenic nerve; Phrenic Nerve; Plague; Yersinia pestis disease; Quality of life; QOL; Rattus; Common Rat Strains; Rat; Rats Mammals; Epidermal Growth Factor Receptor; EGF Receptor; EGFR; ERBB Protein; Epidermal Growth Factor Receptor Kinase; Epidermal Growth Factor Receptor Protein-Tyrosine Kinase; Epidermal Growth Factor-Urogastrone Receptors; HER1; TGF-alpha Receptor; Transforming Growth Factor alpha Receptor; Urogastrone Receptor; c-erbB-1; c-erbB-1 Protein; erbB-1; erbB-1 Proto-Oncogene Protein; erbBl; proto-oncogene protein c-erbB-1; Recurrent Laryngeal Nerve; Rodent; Rodentia; Rodents Mammals; Signal Transduction; Cell Communication and Signaling; Cell Signaling; Intracellular Communication and Signaling; Signal Transduction Systems; Signaling; biological signal transduction; Vertebral column; Spinal Column; Spine; backbone; Survival Rate; Family suidae; Pigs; Suidae; Swine; porcine; suid; Technology; Technology Assessment; Time; Tissues; Body Tissues; Vagus nerve structure; Cranial Nerve X; Pneumogastric Nerve; Tenth Cranial Nerve; Vagus Nerve; Work; falls; improved; Procedures; Site; Clinical; Phase; Ensure; Surgical margins; uptake; Malignant Head and Neck Neoplasm; head/neck cancer; malignant head and neck tumor; Head and Neck Cancer; Collaborations; Letters; Normal tissue morphology; Normal Tissue; Reporter; tool; Life; Hour; Frequencies; Complex; System; Head and neck structure; Head and Neck; Spinal; Operative Surgical Procedures; Operative Procedures; Surgical; Surgical Interventions; Surgical Procedure; surgery; Surgeon; chromophore; experience; Performance; fluorophore; Structure; neurotransmission; Nerve Impulse Transmission; Nerve Transmission; Neuronal Transmission; axon signaling; axon-glial signaling; axonal signaling; glia signaling; glial signaling; nerve signaling; neural signaling; neuronal signaling; novel; Excision; Abscission; Extirpation; Removal; Surgical Removal; resection; Neck Cancer; Malignant Neck Neoplasm; malignant neck tumor; Head Cancer; Modeling; intra-operative imaging; intraoperative imaging; surgical imaging; Image-Guided Surgery; HNSCC; Head and Neck Carcinoma; SCCHN; head and neck squamous carcinoma; head and neck squamous cell cancer; Head and Neck Squamous Cell Carcinoma; small molecule; Length; Dose; Detection; Preclinical Testing; pre-clinical testing; Resolution; resolutions; Cancer Control; Cancer Control Science; Development; developmental; Image; imaging; imaging probe; designing; design; Outcome; constant pain; lasting pain; on-going pain; ongoing pain; Persistent pain; HNC patient; head and neck cancer patient; innovate; innovative; innovation; murine model; mouse model; loss of function; fluorescent imaging; fluorescence imaging; tumor; spared nerve; imaging system; targeted imaging; clinical imaging; clinically translatable; clinical translation; pre-clinical development; preclinical development; imaging capabilities; fluorescence-guided surgery; Injections; surgical outcome; surgery outcome; preservation; Visualization; nerve damage; manufacturing test
