Targeting Melanin in Melanoma with Radionuclide Therapy

Abstract

Nearly 100,000 individuals are expected to be diagnosed with melanoma in the United States in 2022. Treatment options for late-stage metastatic disease up until the 2010s were few and offered only slight improvement to the overall survival. The introduction of B-RAF inhibitors and anti-CTLA4 and anti-PD-1/PD-L1 immunotherapies into standard of care brought measurable increases in the overall survival across all stages of melanoma. Despite the improvement in the survival statistics, patients treated with targeted therapies and immunotherapies are subject to very serious side effects, the development of drug resistance, and the high costs of treatment. This leaves room for the development of novel approaches as well as for the exploration of novel combination therapies for the treatment of metastatic melanoma. One such approach is targeting melanin pigment with radionuclide therapy. Advances in melanin-targeting radionuclide therapy of melanoma can be viewed from two spheres: (1) radioimmunotherapy (RIT) and (2) radiolabeled small molecules. The investigation of mechanisms of the action and efficacy of targeting melanin in melanoma treatment by RIT points to the involvement of the immune system such as complement dependent cytotoxicity. The combination of RIT with immunotherapy presents synergistic killing in mouse melanoma models. The field of radiolabeled small molecules is focused on radioiodinated compounds that have the ability to cross the cellular membranes to access intracellular melanin and can be applied in both therapy and imaging as theranostics. Clinical applications of targeting melanin with radionuclide therapies have produced encouraging results and clinical work is on-going. Continued work on targeting melanin with radionuclide therapy as a monotherapy, or possibly in combination with standard of care agents, has the potential to strengthen the current treatment options for melanoma patients.

Clinical Advances and Perspectives in Targeted Radionuclide Therapy

“…RIT, targeting surface antigens, and PRRT, targeting melanocortin receptors, hardly reached the clinical testing stage. In that context, targeting melanin appeared as particularly attractive [ 259 ]. The melanin pigment is an antigen present in >92% of melanomas [ 260 ].…”

A Theranostic Approach to Imaging and Treating Melanoma with 203Pb/212Pb-Labeled Antibody Targeting Melanin

“…This motivates the development of novel approaches and combination therapies for treating metastatic melanoma. One such approach involves targeting melanin pigment with radionuclide therapy using either melanin-binding small molecules or melanin-specific monoclonal antibodies (mAbs) [12]. Our investigations have targeted melanin with melanin-specific radiolabeled antibodies, a method termed radioimmunotherapy (RIT), as a possible strategy to treat metastatic melanoma [12].…”

“…One such approach involves targeting melanin pigment with radionuclide therapy using either melanin-binding small molecules or melanin-specific monoclonal antibodies (mAbs) [12]. Our investigations have targeted melanin with melanin-specific radiolabeled antibodies, a method termed radioimmunotherapy (RIT), as a possible strategy to treat metastatic melanoma [12]. In mammalian cells, melanin is located intracellularly inside melanosomes.…”

Paradoxical Radiosensitizing Effect of Carnosic Acid on B16F10 Metastatic Melanoma Cells: A New Treatment Strategy

“…In the United States, the incidence rate of melanoma among the white population is much higher than that found among the Hispanic and the black population (5 and 19 times higher, respectively) [ 15 ]. For this reason, it is extremely important to develop new therapeutic arsenals aimed at improving the survival of affected patients [ 16 , 17 ]. Furthermore, it is an aggressive cancer with high resistance to treatment with ionizing radiation and chemotherapy [ 16 , 17 , 18 ].…”

“…For this reason, it is extremely important to develop new therapeutic arsenals aimed at improving the survival of affected patients [ 16 , 17 ]. Furthermore, it is an aggressive cancer with high resistance to treatment with ionizing radiation and chemotherapy [ 16 , 17 , 18 ]. The B16F10 melanoma cell line is a mouse metastatic cell line that is frequently used as a research model of melanomas [ 18 , 19 ].…”