Targeted Theranostics for Metastatic Melanoma

描述(由申请人提供)：美国癌症协会报告称，在过去的30年里，美国的黑色素瘤死亡率一直在上升。它是30岁以下人群中最常见的癌症之一，也是25岁至29岁成年人中最常见的癌症。转移性黑色素瘤细胞被认为是新疗法的潜在靶点，其一个特征是葡萄糖代谢水平升高，并伴随着葡萄糖转运体(如GLUT1)和己糖激酶酶活性的上调。放射性标记葡萄糖(即[18F]-FDG)多年来一直是转移性黑色素瘤的主要成像手段。目前还没有可以检测到黑色素瘤代谢差异的试剂，可以用于成像和靶向放射治疗。这项建议的重点是开发、验证和商业化新型的[203/212]铅标记氨基葡萄糖偶联物(RMX-GC)，用于转移性黑色素瘤的靶向成像和图像引导治疗。我们的创新方法利用配对的~(203)Pb/~(212)Pb，以实现基于~(203)Pb-SPECT成像的明确剂量测定，用于~(212)Pb-α粒子治疗。~(203)Pb/~(212)Pb的半衰期相对较长(51h)，有利于放射性示踪剂的集中生产，~(203)Pb的半衰期为10h，可通过区域治疗中心实现商业化。RadioMedex公司与视点分子靶向有限责任公司建立了强大的业务合作伙伴关系，使我们能够对诊断SPECT放射性示踪剂203Pb-RMX-GC进行详细评估，随后验证放射治疗剂212Pb-RMX-GC。我们的总体目标是开发有效的治疗转移性黑色素瘤的方法，以改善黑色素瘤的诊断和临床结果，并比目前的治疗方法副作用更少。为了实现这些目标，我们提出了以下具体目标：1.发展和优化~(203)Pb DOTA-氨基葡萄糖的放射合成；2.测定~(203)Pb DOTA-氨基葡萄糖在荷黑色素瘤小鼠的体内药效学；3.记录~(203)Pb-DOTA-RMX-GC试剂盒的制造和质量控制协议，并证明[~(203)Pb]DOTA-RMX-GC偶联的稳定性。随着这些目标的成功完成，我们希望证明使用203Pb/212Pb-RMX-GC试剂进行成像的可行性，并随后用于图像引导治疗转移性黑色素瘤。这些结果将支持我们在IND申报和未来第二阶段SBIR提交的规模化制造和毒理学研究方面的进一步投资。

DESCRIPTION (provided by applicant): The American Cancer Society reports that death rates for melanoma have been rising in the United States for the past 30 years. It is one of the more common cancers in population younger than 30, and the most common cancer in adults ages 25 to 29. One characteristic of metastatic melanoma cells that is recognized as a potential target for new therapies is their elevated glucose metabolism - and concomitant upregulation of glucose transporters (e.g., GLUT1) and hexokinase enzyme activity. Radiolabeled glucose (i.e., [18F]-FDG) has been the mainstay for imaging of metastatic melanoma for many years. There are no agents available that detect differences in melanoma metabolism and can be used for both imaging and targeted radiotherapy. This proposal is focused on development, validation and commercialization of novel class of theranostic [203/212]Pb-labeled glucosamine conjugates (RMX-GC) for targeted imaging and image-guided therapy of metastatic melanoma. Our innovative approach enlists matched-pair isotopes 203Pb/212Pb to enable unambiguous dosimetry based on 203Pb-SPECT imaging for 212Pb-alpha-particle therapy. [203Pb/212Pb] are attractive also due to a relatively long half-life (51 h) of 203Pb, which is favorable for centralized manufacturing of radiotracers and a 10 h half-life of 212Pb, which can be commercialized through regional therapy centers. RadioMedix Inc. has developed a strong business-partnership with ViewPoint Molecular Targeting LLC that allow us for detailed evaluation of the diagnostic SPECT radiotracer, 203Pb-RMX-GC, followed by validation of the radiotherapeutic agent, 212Pb-RMX-GC. Our overall objective is to develop effective theranostic approach for metastatic melanoma that improves diagnosis of melanoma and clinical outcomes with fewer-milder side effects than current therapies. To achieve these objectives, we propose the following specific aims: 1. Develop and optimize the radio synthesis of 203Pb DOTA-glucosamines; 2. Determine the in vivo pharmacodynamics of 203Pb DOTA-glucosamines in melanoma- tumor-bearing mice; 3. Document protocols for manufacturing and quality control of 203Pb-DOTA-RMX-GC kits and demonstrate the stability of the [203Pb]DOTA-RMX-GC coupling. With successful completion of these aims, we expect to demonstrate the feasibility of using 203Pb/212Pb- RMX-GC agents for imaging and later on image-guided therapy for metastatic melanoma. These results will support our further investment in scaled manufacturing and toxicology studies for our IND filings and future Phase II SBIR submissions.