Clinical Translation of a Choline-targeted NIR dye to guide lung cancer resection - The major goal of this project is to complete IND-enabling studies required by the FDA for our candidate fluorophore, JAS239, and to utilize it in a first in human (FIH) clinical trial for fluorescence-guided resections of lung tumors. JAS239 is a Choline Kinase α (ChoKα) inhibitor that fluoresces in the near-infrared (NIR), making it ideal for intraoperative imaging of cancer. ChoKα is a lipid enzyme overexpressed in up to 85% of non-small cell lung carcinomas (NSCLCs), for which the standard of care is surgical resection. Surgeons typically use visual inspection and finger palpation to identify lung tumors and their margins, however these methods are often insufficient for identification of primary deep tissue tumors, tumor margins, and synchronous lesions, leading to tumor recurrence in approximately 40% of surgical patients. Thus, new optical techniques are needed to aid surgeons in identifying malignant disease. Intraoperative fluorescence imaging offers support to surgeons in identifying tumor lesions and has been shown to improve surgical outcomes. While recent years have shown an increase in the development of new targeted fluorophores for intraoperative cancer detection, additional targeted fluorophores are needed to account for the heterogeneity and complexity of malignant diseases. In this application, we will test the hypothesis that JAS239 is safe in preclinical models and humans, has acceptable ADME properties, and can be used to identify tumors in order to improve surgical outcomes in patients presenting with NSCLC. Aim 1: Complete preclinical IND-enabling studies. As advised by the FDA, we will conduct IND-enabling studies with JAS239, including assessment of phototoxicity, determination of in vitro genotoxicity and further repeat dose toxicity studies in mice and dogs. Any studies outside the scope of our lab will be contracted to a certified third-party company (Charles River Laboratories). Aim 2: Acquire cGMP-compliant JAS239. We will contract Leiden University Medical Center (LUMC) Center for Human Drug Research (CHDR) to synthesize JAS239 under cGMP conditions. Aim 3: Obtain an IND from the FDA. In accordance with FDA and ICH guidelines and in coordination with the University of Pennsylvania Abramson Cancer Center Clinical Trials Unit and the Center for Precision Surgery (CPS), the proposed clinical trial design, preclinical POC studies, two-species pharmacology/toxicology results, in vitro genotoxicity studies, chemistry, manufacturing, and controls (CMC) documentation, and canine clinical trial data will be submitted as an IND application package to the FDA. Aim 4: Conduct Phase IA and IB clinical trial with JAS239. We will initiate a Phase IA and IB clinical trial with the Center for Precision Surgery at the University of Pennsylvania to determine the safety profile, PK/BD, and metabolism of JAS239 in healthy human volunteers and human patients with NSCLC who will undergo tumor resection under fluorescence guidance.
