NEAR-INFRARED FLUORESCENT CHOLINE KINASE ALPHA INHIBITOR FOR INTRAOPERATIVE LUNG CANCER IMAGING

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Degree type
Doctor of Philosophy (PhD)
Graduate group
Pharmacology
Discipline
Pharmacology, Toxicology and Environmental Health
Subject
Cancer
Choline kinase
Fluorescence
Imaging
NIR
Optical
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2022
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Osharovich, Sofya
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Abstract

ABSTRACT NEAR-INFRARED FLUORESCENT CHOLINE KINASE ALPHA INHIBITOR FOR INTRAOPERATIVE LUNG CANCER IMAGING Choline Kinase α (ChoKα) is an established cancer biomarker associated with an aggressive phenotype, high histological tumor grade, and poor clinical outcome in many human cancers. ChoKα is overexpressed in 60% of human lung tumors. ChoKα catalyzes the phosphorylation of choline to generate phosphocholine, a precursor of the cell membrane phospholipid, phosphatidylcholine (PtdCho). A novel near-infrared (NIR) fluorescent ChoKα inhibitor, JAS239 (ex: 745 nm, em: 775 nm), has been developed. JAS239 binds to the active site of ChoKα, competitively inhibiting phosphocholine production. The intraoperative standard of care for identifying tumors is palpation and visual inspection along with the aid of preoperative scans. However, this approach is insufficient, as surgeons often miss occult lesions and locoregional metastases which results in local recurrence in up to 40% of patients and a significantly reduced 5-year survival. This problem can be mediated with the use of fluorophores for optical surgical navigation. Presently, there are a limited number of FDA-approved targeted NIR fluorophores and none that target ChoKα. We hypothesize that JAS239 can be used to target ChoKα-overexpressing tumors for optical surgical navigation in small and large animal models of lung cancer. Presented here is the characterization of JAS239 in a ChoKα-overexpressing lung cancer cell line, in a mouse model of lung cancer, in pharmacokinetic and pharmacodynamic studies, and in a canine clinical trial. Canine patients with spontaneous operable lung adenocarcinomas were recruited into an informed consent clinical trial. Fluorescence imaging of the lung tumors was performed in situ and ex vivo. Sections of the tumors were cut and imaged on the back table and submitted to pathology for hematoxylin and eosin (H&E) staining and ChoKα immunohistochemistry (IHC). Intraoperative tumor imaging showed clear margin delineation. IHC showed heterogeneous ChoKα expression, similar to what is seen in humans. The aim of these studies is to establish JAS239 as a suitable imaging agent for optical surgical navigation in lung tumors with the goal of translating JAS239 into human lung tumor patients.

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Delikatny, Edward, J
Date of degree
2022
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