Novel Receptor-Targeting Peptides for Melanoma Therapy

恶性黑色素瘤是最致命的皮肤癌，其发病率在美国呈上升趋势。 各州。不幸的是，转移性黑色素瘤还没有根治方法。尽管取得了显著的进步， 分子靶向治疗转移性黑色素瘤多年来长期存活 保持10%。因此，迫切需要开发新的转移性黑色素瘤的治疗策略。 黑素皮质素-1受体(MC1R)是一个独特的分子靶点，因为它在人类80%的细胞上过度表达 转移性黑色素瘤。我们开发了一类新型的MC1R靶向内酰胺环化CycMSHhex 用于黑色素瘤成像的多肽。关于可视的首例人类临床结果 用我们的CycMSHhex多肽转移黑色素瘤清楚地表明了MC1R的临床意义 黑色素瘤成像，以及强调迫切需要开发MC1R靶向治疗药物 治疗转移性黑色素瘤患者。因此，我们建议开发新型的靶向MC1R的治疗药物 (诊断和治疗)用于影像引导治疗的⁰-PbDOTA-Linker-NLE-CycMSHhex 这个项目中的黑色素瘤。我们推测DOTA-Linker-NLE-CycMSHhex多肽可以与 MC1Rs和靶向配对放射治疗(⁰)与人类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)连接物来改善黑色素瘤的摄取和清除 的性质，然后检查选定的⁰的治疗效果。 在这个项目中，在人类黑色素瘤异种移植和转移中的铅-DOTA-Linker-NLE-CycMSHhex多肽。 我们的新型CycMSHhex多肽获得了4项美国专利，展示了我们的原创性和 这个项目的新颖性。 本项目的目标是开发新型的以MC1R为靶标的热敏⁰-PbDOTA-Linker-NLE- CycMSHhex多肽通过影像引导治疗转移性黑色素瘤。我们积极的初步结果 强烈支持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 拥有成熟的专业知识，特别适合执行这一令人兴奋的翻译项目。的成功之处 该项目将提供一种新的成像工具(Pb肽)来识别将受益的⁰阳性患者 以确定安全和有效的剂量，并监测患者对 治疗。此外，该项目的成功将为转移性黑色素瘤的治疗开辟道路。 受体靶向阿尔法疗法与未来其他治疗方法的结合，提供 具有个性化诊断和治疗的患者。本项目中新的抗癌多肽的鉴定 将为在美国FDA批准的临床上评估这种新型多肽放射性药物铺平道路 在未来进行试验，并增加转移性黑色素瘤患者的治疗机会。

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.