BPS 2018
225Ac-DOTA-MC1RL as a novel therapy for metastatic uveal melanoma
Mark McLaughlin
Mark, Modulation Therapeutics Inc
ABSTRACT
New effective therapies are greatly needed for metastatic uveal melanoma, which has a very poor prognosis with a median survival of less than one year. The melanocortin 1 receptor (MC1R) is expressed in 94% of uveal melanoma metastases and 225Ac-DOTA-MC1RL conjugate was synthesized in high radiochemical yield and purity, tested in vitro for biostability, MC1R-specific cytotoxicity in uveal melanoma cells, and the La-DOTA-MC1RL analog was tested for binding affinity. In vivo studies tested non-tumor bearing BALB/c mice for maximum tolerated dose and biodistribution, and SCID mice bearing uveal melanoma tumors and engineered MC1R positive and negative tumors for biodistribution and efficacy. Radiation dosimetry and pharmacokinetics were calculated using the biodistribution and blood clearance data from Sprague-Dawley rats. Limiting toxicities were not observed at even the highest administered activities. Pharmacokinetics and biodistribution studies revealed rapid blood clearance (<15 min), renal and hepatobillary excretion, MC1R specific tumor uptake and minimal retention in other normal tissues. Radiation dosimetry calculations determined pharmacokinetics parameters and absorbed α-emission dosages from 225Ac and its daughters. Efficacy studies demonstrated significantly prolonged survival and decreased metastasis burden following a single administration of 225Ac-DOTA-MC1RL in treated mice relative to controls. These results suggest significant potential for the clinical translation of 225Ac-DOTA-MC1RL as a novel therapy for metastatic uveal melanoma.
BIO
Mark L. McLaughlin, Professor of Medicinal Chemistry, Department of Pharmaceutical Sciences, B.S., Chemistry, Christian Brothers University, Ph.D., Organic Chemistry, Georgia Institute of Technology. After postdoctoral appointments at Rice and Ohio State Universities, he was promoted through the ranks to Professor of Chemistry, Louisiana State University. In 2002, he moved to Professor of Chemistry and Oncological Sciences, University of South Florida, Senior Member, Drug Discovery Department, Moffitt Cancer Center. McLaughlin’s research group is pursuing anticancer drug discovery and development focused on protein-protein interaction inhibitor design, molecularly targeted radiotherapy, and molecularly targeted immunotherapy for the treatment/cure of targeted cancers.