Abstract
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Objectives CLR1404 (aka NM404) is a diapeutic phospholipid ether analogue characterized by preferential tumor uptake and prolonged retention in 52/54 preclinical tumor models, including gliomas. Isosteric iodine substitution in CLR1404 affords either a diagnostic/imaging agent (e.g. 124I for PET imaging) or a molecular radiotherapeutic agent (e.g. 131I for cancer-selective cytotoxicity). CLR1404 enters malignant cells via membrane lipid rafts which are overexpressed in cancer cells. The purpose of this study is to demonstrate the first successful use of 124I CLR1404 PET/CT in humans with primary and metastatic brain tumors.
Methods Eight patients with brain tumors, 2 new diagnosis (1 high grade glioma (HGG) & 1 metastasis (mets)) and 6 tumor recurrence verses treatment change (3 HGG (including one patient with both HGG and atypical meningioma) and 3 low grade gliomas (LGG)) were injected with 74 to 185 MBq of 124I-CLR1404 and imaged over multiple time points. PET was compared to MRI and tumor to background ratios (T:B) were calculated.
Results MRI scans demonstrated enhancement in 6 patients and no ehancement in 2 patients (both with LGG) with tumor sizes varying from 0.7 x 1.2 cm to 3.1 x 5.4 cm. Six patients had increased T2/FLAIR signal from previous treatment changes. 124I-CLR1404 PET scans demonstrated significant tumor uptake in all 4 HGG, 1 mets, 1 atypical meningioma, and 1 LGG. Two LGG did not have CLR1404 uptake (1 with stable MRI and 1 with followup pending). Areas of concordant and discordant MRI enhancement, T2 FLAIR, and PET uptake were present. There was no significant background uptake in normal brain or in previously radiated brain that was tumor-free. Average T:B ratios increased over time and were 5.7 at 6 hours, 9.4 at 1 day, 13.1 at 2 days, and 15.1 at 5 days.
Conclusions 124I-CLR1404 PET/CT successfully images brain tumors in humans and demonstrates significant tumor to background uptake and prolonged retention. These attributes make this novel agent a promising “diapeutic” candidate for brain tumors.
Research Support NIH/NCI: 1 R01 CA158800 National Center for Advancing Translational Sciences (NCATS): 9U54TR000021 University of Wisconsin Carbone Cancer Center Pilot Grant