Novel Receptor-Targeting Peptides for Melanoma Therapy

用于黑色素瘤治疗的新型受体靶向肽

• 批准号: 9899954
• 负责人: Yubin Miao
• 金额: $ 39.08万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-04-01 至 2023-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9899954
• 关键词: Acids; Affinity; Award; BRAF gene; Binding; Biodistribution; CTLA4 gene; Cells; Clinical; Clinical Trials; Diagnostic; Dose; FDA approved; Future; Human; Hydrocarbons; Image; Imaging Device; Incidence; Kidney; Label; Lactams; Legal patent; Maximum Tolerated Dose; Melanocortin 1 Receptor; Melanoma Cell; Metastatic Melanoma; Modeling; Molecular Target; Neoplasm Metastasis; Nude Mice; Organ; Patient Monitoring; Patients; Peptides; Polyethylene Glycols; Property; Radiopharmaceuticals; Research; Research Design; Skin Cancer; Therapeutic; Treatment Efficacy; United States; Visualization; Xenograft procedure; alternative treatment; clinically significant; curative treatments; dosimetry; first-in-human; image guided therapy; improved; lung metastatic; melanoma; novel; originality; overexpression; personalized diagnostics; personalized medicine; programmed cell death protein 1; radiotracer; receptor; receptor binding; success; targeted treatment; theranostics; treatment response; treatment strategy; tumor; uptake

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 advance of molecularly targeted approaches in treating metastatic melanoma over the past years, the long-term survival remains <10%. Thus, there is an urgent need to develop new treatment strategies for metastatic melanoma. Melanocortin-1 receptor (MC1R) is a distinct molecular target due to its over-expression on >80% of human metastatic melanomas. We have developed a novel class of MC1R-targeting lactam-cyclized CycMSHhex peptides for melanoma imaging. The remarkable first-in-man clinical results regarding the visualization of melanoma metastases using our CycMSHhex peptide clearly demonstrate the clinical significance of MC1R in melanoma imaging, as well as underscore the urgent need to develop MC1R-targeting therapeutic agents for treating patients with metastatic melanoma. Thus, we propose to develop novel MC1R-targeting theranostic (diagnostic & therapeutic) ²⁰³Pb/²¹²Pb-DOTA-Linker-Nle-CycMSHhex peptides for imaging-guided therapy of melanoma in this project. We hypothesize that DOTA-Linker-Nle-CycMSHhex peptides can specifically bind to MC1Rs and target matched-pair theranostic ²⁰³Pb/²¹²Pb to human melanoma cells for imaging-guided therapy. We will use hydrocarbon and polyethylene glycol (PEG) linkers to improve melanoma uptake and clearance properties of ²⁰³Pb/²¹²Pb-DOTA-Linker-Nle-CycMSHhex, and then examine the therapeutic efficacies of selected ²¹²Pb-DOTA-Linker-Nle-CycMSHhex peptides in human melanoma xenografts and metastases in this project. We have been awarded 4 US patents for our novel CycMSHhex peptides, demonstrating the originality and novelty of this project. The objective of this project is to develop novel MC1R-targeting theranostic ²⁰³Pb/²¹²Pb-DOTA-Linker-Nle- CycMSHhex peptides to treat metastatic melanoma via imaging-guided therapy. 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 success of this project will provide a novel imaging tool (²⁰³Pb-peptide) to identify MC1R-positive patients who will benefit from ²¹²Pb-peptide treatments, to determine safe and efficacious doses, and to monitor patients' responses to treatments. Moreover, the success of this project will open the avenue of treating metastatic melanoma with the combination of receptor-targeted alpha therapy (²¹²Pb-peptide) and other treatments in the future, providing patients with personalized diagnoses and treatments. Identification of novel theranostic peptides in this project will pave the way for evaluating this novel class of peptide radiopharmaceuticals in US FDA-approved clinical trials in the future, and enhance the opportunities of cures to patients with metastatic melanoma.

恶性黑色素瘤是皮肤癌中最致命的一种，在美国发病率越来越高