Melanocortin 1 Receptor-Targeted α-Particle Therapy for Metastatic Uveal Melanoma

Narges K Tafreshi; Christopher J Tichacek; Darpan N Pandya; Michael L Doligalski; Mikalai M Budzevich; HyunJoo Kil; Nikunj B Bhatt; Nancy D Kock; Jane L Messina; Epifanio E Ruiz; Nella C Delva; Adam Weaver; William R Gibbons; David C Boulware; Nikhil I Khushalani; Ghassan El-Haddad; Pierre L Triozzi; Eduardo G Moros; Mark L McLaughlin; Thaddeus J Wadas; David L Morse

doi:10.2967/jnumed.118.217240

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Melanocortin 1 Receptor-Targeted α-Particle Therapy for Metastatic Uveal Melanoma

Journal article

Open access

Peer reviewed

Melanocortin 1 Receptor-Targeted α-Particle Therapy for Metastatic Uveal Melanoma

Narges K Tafreshi, Christopher J Tichacek, Darpan N Pandya, Michael L Doligalski, Mikalai M Budzevich, HyunJoo Kil, Nikunj B Bhatt, Nancy D Kock, Jane L Messina, Epifanio E Ruiz, …

The Journal of nuclear medicine (1978), Vol.60(8), pp.1124-1133

08/2019

DOI: 10.2967/jnumed.118.217240

PMCID: PMC6681690

PMID: 30733316

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Abstract

New effective therapies are greatly needed for metastatic uveal melanoma, which has a very poor prognosis with a median survival of less than 1 y. The melanocortin 1 receptor (MC1R) is expressed in 94% of uveal melanoma metastases, and a MC1R-specific ligand (MC1RL) with high affinity and selectivity for MC1R was previously developed. The Ac-DOTA-MC1RL conjugate was synthesized in high radiochemical yield and purity and was tested in vitro for biostability and for MC1R-specific cytotoxicity in uveal melanoma cells, and the lanthanum-DOTA-MC1RL analog was tested for binding affinity. Non-tumor-bearing BALB/c mice were tested for maximum tolerated dose and biodistribution. Severe combined immunodeficient mice bearing uveal melanoma tumors or engineered MC1R-positive and -negative tumors were studied for biodistribution and efficacy. Radiation dosimetry was calculated using mouse biodistribution data and blood clearance kinetics from Sprague-Dawley rat data. High biostability, MC1R-specific cytotoxicity, and high binding affinity were observed. 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 Ac and its daughters. Efficacy studies demonstrated significantly prolonged survival and decreased metastasis burden after a single administration of Ac-DOTA-MC1RL in treated mice relative to controls. These results suggest significant potential for the clinical translation of Ac-DOTA-MC1RL as a novel therapy for metastatic uveal melanoma.

Alpha Particles

Animals

Antineoplastic Agents - pharmacology

Cell Line, Tumor

Chelating Agents - chemistry

Female

Humans

Lanthanoid Series Elements - chemistry

Male

Maximum Tolerated Dose

Melanoma - radiotherapy

Mice

Mice, Inbred BALB C

Mice, SCID

Molecular Targeted Therapy

Neoplasm Metastasis

Neoplasm Transplantation

Prognosis

Radiometry

Radiopharmaceuticals - pharmacokinetics

Rats

Rats, Sprague-Dawley

Receptor, Melanocortin, Type 1 - chemistry

Uveal Neoplasms - radiotherapy

Details

Title: Subtitle: Melanocortin 1 Receptor-Targeted α-Particle Therapy for Metastatic Uveal Melanoma
Creators: Narges K Tafreshi - Moffitt Cancer Center
Christopher J Tichacek - University of South Florida
Darpan N Pandya - Wake Forest University
Michael L Doligalski - Moffitt Cancer Center
Mikalai M Budzevich - Moffitt Cancer Center
HyunJoo Kil - Modulation Therapeutics
Nikunj B Bhatt - Wake Forest University
Nancy D Kock - Wake Forest University
Jane L Messina - University of South Florida
Epifanio E Ruiz - Moffitt Cancer Center
Nella C Delva - Moffitt Cancer Center
Adam Weaver - University of South Florida
William R Gibbons - University of South Florida
David C Boulware - Moffitt Cancer Center
Nikhil I Khushalani - Moffitt Cancer Center
Ghassan El-Haddad - Moffitt Cancer Center
Pierre L Triozzi - Wake Forest University
Eduardo G Moros - Moffitt Cancer Center
Mark L McLaughlin - Modulation Therapeutics
Thaddeus J Wadas - Wake Forest University
David L Morse - Moffitt Cancer Center
Resource Type: Journal article
Publication Details: The Journal of nuclear medicine (1978), Vol.60(8), pp.1124-1133
DOI: 10.2967/jnumed.118.217240
PMID: 30733316
PMCID: PMC6681690
NLM abbreviation: J Nucl Med
ISSN: 0161-5505
eISSN: 1535-5667
Grant note: U54 GM104942 / NIGMS NIH HHS P30 CA076292 / NCI NIH HHS
Language: English
Date published: 08/2019
Academic Unit: Radiology; Radiation Oncology
Record Identifier: 9984312961702771

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