Wednesday, January 15, 2025
1/15/2025
ABSTRACT Malignant melanoma is the most lethal form of skin cancer with an increasing incidence in the United States. Unfortunately, no curative treatment exists for metastatic melanoma. Despite the significant advances of molecularly targeted treatments (BRAF-, CTLA-4- and PD-1-targeted therapies) in treating metastatic melanoma over the past decade, the 5-year survival is only 35% for metastatic melanoma patients. Thus, there is an urgent need to develop alternative treatment strategies for metastatic melanoma. Melanocortine-1 receptor (MC1R) is a distinct molecular target due to its high expression in >80% of melanotic and amelanotic human metastatic melanoma. Our remarkable first-in-human results clearly demonstrate the feasibility of using MC1R-targeted 68Ga-DOTA-GGNle-CycMSHhex for human melanoma imaging. Recently, we have identified DOTA-GGNle-CycMSHhex(KD) peptide with 0.12 nM MC1R binding affinity which is dramatically improved by 8.3-fold as compared to DOTA-GGNle-CycMSHhex. Moreover, the replacement of -GG- with 8-Aminooctanoic acid (-Aoc-) linker further improves the MC1R binding affinity of DOTA-AocNle-CycMSHhex(KD) peptide by 3.8-fold as compared to DOTA-GGNle-CycMSHhex(KD). Thus, we propose to develop novel theranostic 203Pb/212Pb-DOTA-Linker-Nle-CycMSHhex(KD) peptides for imaging- guided MC1R-targeted alpha radionuclide therapy (MC1R-TART), and combine them with immune checkpoint inhibitors (ICIs) for melanoma treatment in this project. We hypothesize that novel theranostic 203Pb/212Pb- DOTA-Linker-Nle-CycMSHhex(KD) peptides can be used for imaging-guided MC1R-TART, and the combinations of MC1R-TART and ICIs can treat melanoma more effectively than MC1R-TART only. The objective of this project is to develop novel theranostic 203Pb/212Pb-DOTA-Linker-Nle-CycMSHhex(KD) peptides imaging-guided MC1R-TART, and combine MC1R-TART with ICIs for melanoma treatment. Our awarded US patents clearly demonstrate the originality and novelty of this project. Our positive preliminary results strongly support our hypothesis and research design. Importantly, we have assembled a strong research team with established expertise that is uniquely suited to carry out this exciting translational project. The positive results of this project will demonstrate the feasibility and efficacy of combining MC1R-TART and ICIs for melanoma treatment, and provide a new insight into the design of novel treatments for metastatic melanoma. The success of this project will provide clinicians a novel valuable imaging tool (203Pb-peptide) to identify MC1R-positive patients who will benefit from the treatments, determine patient-specific dosimetry for safe and efficacious doses, and monitor patients’ responses to MC1R-TART and ICIs treatments. The success of this project will pave the way for evaluating this novel treatment in future FDA-approved clinical trials, provide patients with personalized diagnoses and treatments, enhancing the opportunity for cure to metastatic melanoma patients.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).