Translating phospholipase activatable fluorophores for the sensitive detection of non-small cell lung cancer

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PROJECT SUMMARY This application proposes to translate activatable fluorophores targeted to cytosolic phospholipase A2α (cPLA2α) for intraoperative surgical detection in lung cancer. Lung cancer is the leading cancer-related cause of death and the third most diagnosed cancer in the United States. Non-small cell lung carcinomas (NSCLC), represent 90% of lung cancers, and surgical resection continues to be the most effective approach to cure patients with low stage premetastatic disease. Surgeons typically use visual inspection and finger palpation to define solid tumor margins. However, this approach is often insufficient to detect residual disease, leading to recurrence in up to 40% of patients and significantly reduced 5-year survival. Improving intraoperative detection of tumor margins is imperative, because small foci of residual disease at or close to the resection margins are the most common cause of local recurrence. The most important prognostic indicator following cancer surgery is complete resection, which prolongs patient survival and improves post- surgical quality of life. Contrast enhancement of tumors using near-infrared (NIR) imaging with targeted fluorophores can identify small lesions that are not detectable by visual observation or palpation. NIR imaging offers high resolution and sensitivity and can be performed in real-time during surgery. In this application, we propose to translate DDAO-arachidonate (DDAO-A), an activatable probe designed to specifically target cPLA2α, a critical signaling enzyme upregulated early in tumorigenesis and overexpressed in more than 47% of NSCLC. Preliminary Studies indicate that DDAO-A is selectively activated by murine and human NSCLC tumors, and can detect small foci in both mouse models and excised human lung tumor tissue. DDAO-A will be synthesized under GLP conditions and dispersed in clinically approved liposomal formulations for delivery. Selected mouse studies will be performed to confirm probe activation, tumor targeting and the ability to detect tumor margins. Systemic toxicity will be evaluated in mice and in a small cohort of canines. We will utilize an established platform for clinical translation of NIR fluorophores, employing a canine clinical trial for intraoperative surgery. We will recruit a patient cohort of 30 companion animals with spontaneous NSCLC presenting to our Veterinary School. DDAO-A will be used for detection of primary tumors and identification of tumor margins during intraoperative fluorescence-guided surgery (FGS) in canine patients. We will investigate both systemic injection and topical application for detection of residual tumor. These data will be compared to control surgical cohorts using the non-targeted indocyanine green (ICG) or without NIR fluorescence guidance. If successful, this study will improve surgical outcomes by improving localization of small tumor deposits in the lung, lymph nodes and margins. The completion of these studies will form the basis for an investigational new drug (IND) application in support of a clinical trial to assess DDAO-A-guided surgery in human lung cancer patients.