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Efficacy of Targeted Radionuclide Therapy Using [131I]ICF01012 in 3D Pigmented BRAF- and NRAS-Mutant Melanoma Models
Hussein Akil1,2, Mercedes Quintana1, Jérémy H Raymond3,4,5
1INSERM U1240, University of Clermont Auvergne, 58 rue Montalembert, 63000 Clermont-Ferrand, France.
Purpose:
To assess the efficiency of targeted radionuclide therapy (TRT), alone or in combination with MEK inhibitors (MEKi), in melanomas harboring constitutive MAPK/ERK activation responsible for tumor radioresistance.
Methods:
For TRT, we used a melanin radiotracer ([131I]ICF01012) currently in phase 1 clinical trial (NCT03784625). TRT alone or combined with MEKi was evaluated in three-dimensional melanoma spheroid models of human BRAFV600E SK-MEL-3, murine NRASQ61K 1007, and WT B16F10 melanomas. TRT in vivo biodistribution, dosimetry, efficiency, and molecular mechanisms were studied using the C57BL/6J-NRASQ61K 1007 syngeneic model.
Results:
TRT cooperated with MEKi to increase apoptosis in both BRAF- and NRAS-mutant spheroids. NRASQ61K spheroids were highly radiosensitive towards [131I]ICF01012-TRT. In mice bearing NRASQ61K 1007 melanoma, [131I]ICF01012 induced a significant extended survival (92 vs. 44 days, p < 0.0001), associated with a 93-Gy tumor deposit, and reduced lymph-node metastases. Comparative transcriptomic analyses confirmed a decrease in mitosis, proliferation, and metastasis signatures in TRT-treated vs. control tumors and suggest that TRT acts through an increase in oxidation and inflammation and P53 activation.
Conclusion:
Our data suggest that [131I]ICF01012-TRT and MEKi combination could be of benefit for advanced pigmented BRAF-mutant melanoma care and that [131I]ICF01012 alone could constitute a new potential NRAS-mutant melanoma treatment.
Insights
Targeted radionuclide therapy (TRT) with [131I]ICF01012 shows promise for melanoma. TRT combined with MEK inhibitors (MEKi) benefits BRAF-mutant melanoma, while TRT alone may treat NRAS-mutant melanoma.
Area of Science:
- Oncology
- Radiopharmaceutical Therapy
- Molecular Biology
Background:
- Melanoma often exhibits constitutive MAPK/ERK activation, leading to tumor radioresistance.
- Targeted radionuclide therapy (TRT) offers a potential strategy to overcome radioresistance.
- MEK inhibitors (MEKi) can modulate MAPK/ERK signaling pathways.
Purpose of the Study:
- To evaluate the efficacy of [131I]ICF01012-based TRT, alone and combined with MEKi, in melanoma models.
- To investigate the impact of TRT on melanomas with constitutive MAPK/ERK activation.
- To assess the therapeutic potential in BRAF-mutant and NRAS-mutant melanoma.
Main Methods:
- Utilized three-dimensional melanoma spheroid models (BRAFV600E, NRASQ61K, WT).
- Administered [131I]ICF01012 TRT, alone and in combination with MEKi.
- Conducted in vivo studies using a C57BL/6J-NRASQ61K 1007 syngeneic model, including biodistribution, dosimetry, and transcriptomic analysis.
Main Results:
- TRT combined with MEKi enhanced apoptosis in both BRAF- and NRAS-mutant melanoma spheroids.
- [131I]ICF01012-TRT significantly improved survival in mice with NRASQ61K melanoma (92 vs. 44 days).
- TRT reduced lymph-node metastases and decreased proliferation and metastasis signatures, suggesting P53 activation and increased oxidation/inflammation.
Conclusions:
- The combination of [131I]ICF01012-TRT and MEKi may benefit advanced pigmented BRAF-mutant melanoma.
- [131I]ICF01012 alone represents a potential new treatment for NRAS-mutant melanoma.
- TRT demonstrates efficacy in overcoming radioresistance and reducing melanoma metastasis.
