Novel Receptor-Targeting Peptides for Melanoma Therapy

恶性黑色素瘤是最致命的皮肤癌，在美国的发病率越来越高。 States.不幸的是，对于转移性黑色素瘤不存在治愈性治疗。尽管取得了重大进展， 在过去的几年里，分子靶向方法治疗转移性黑色素瘤， 仍然<10%。因此，迫切需要开发新的转移性黑色素瘤治疗策略。 黑素皮质素-1受体（Melanocortin-1 receptor，MC 1 R）是一种独特的分子靶点，因为其在超过80%的人类肿瘤细胞中过表达。 转移性黑素瘤我们开发了一类新型的MC 1 R靶向内酰胺环化CycMSHhex 用于黑素瘤成像的肽。关于可视化的显著的首次人体临床结果 使用我们的CycMSHhex肽的黑色素瘤转移清楚地证明了MC 1 R在 黑色素瘤成像，以及强调迫切需要开发MC 1 R靶向治疗剂， 治疗转移性黑色素瘤患者因此，我们建议开发新的MC 1 R靶向治疗诊断剂， （诊断和治疗）² ² ³Pb/² ² ²Pb-DOTA-Linker-Nle-CycMSHhex肽用于成像引导治疗 黑色素瘤在这个项目中。我们假设DOTA-连接体-Nle-CycMSHhex肽可以特异性地结合至 MC 1 R和靶向配对治疗诊断剂Pb对人黑色素瘤细胞进行成像引导治疗。 我们将使用碳氢化合物和聚乙二醇（PEG）连接剂来改善黑色素瘤的吸收和清除 的性质，然后检查所选的治疗效果。 Pb-DOTA-Linker-Nle-CycMSHhex肽在本项目中用于人黑素瘤异种移植物和转移瘤。 我们的新型CycMSHhex肽已获得4项美国专利，证明了我们的原创性和 这个项目的新奇。 本项目的目标是开发新型MC 1 R靶向治疗诊断剂<$L3Pb/<$L3 Pb-DOTA-Linker-Nle- CycMSHhex肽通过成像引导疗法治疗转移性黑色素瘤我们积极的初步结果 有力地支持了我们的假设和研究设计。重要的是，我们组建了一支强大的研究团队， 拥有独特的专业知识，非常适合执行这一令人兴奋的翻译项目。的成功 该项目将提供一种新的成像工具（铅肽）来识别MC 1 R阳性患者， 从铅肽治疗，以确定安全和有效的剂量，并监测患者的反应， 治疗。此外，该项目的成功将开辟治疗转移性黑色素瘤的途径， 结合受体靶向α治疗（铅肽）和其他治疗在未来， 患者的个性化诊断和治疗。本项目中新型治疗诊断肽的鉴定 将为在美国FDA批准的临床试验中评估这类新型肽放射性药物铺平道路。 在未来的试验，并提高治愈转移性黑色素瘤患者的机会。

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.