Targeted Theranostics for Metastatic Melanoma

转移性黑色素瘤的靶向治疗诊断

• 批准号: 8711936
• 负责人: Izabela Tworowska
• 金额: $ 14.99万
• 依托单位: RADIOMEDIX, INC.
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-07-25 至 2015-01-24
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8711936
• 关键词: Adult; Adverse effects; Age; Alpha Particles; American Cancer Society; Biodistribution; Businesses; Cancerous; Cell Therapy; Cells; Characteristics; Chemicals; Clinic; Clinical; Clinical Trials; Coupling; Cyclic GMP; Data; Death Rate; Development; Diagnosis; Diagnostic; Diagnostic Imaging; Disease; Documentation; Dose; Drug Formulations; Evaluation; Excretory function; Funding; Future; Glucosamine; Glucose; Glucose Transporter; Half-Life; Image; Incidence; Investments; Isotopes; Kidney; Knowledge; Label; Lead; Life Expectancy; Maintenance; Malignant Neoplasms; Manufacturer Name; Marketing; Medical Imaging; Melanoma Cell; Metabolism; Metastatic Melanoma; Molecular Target; Mus; Non-Malignant; Normal Cell; Nuclear; Operative Surgical Procedures; Organ; Orphan; Orphan Drugs; Outcome; Patients; Pharmaceutical Preparations; Pharmacodynamics; Phase; Phase I Clinical Trials; Population; Positron; Preparation; Process; Production; Property; Protocols documentation; Published Comment; Qualifying; Quality Control; Quality of life; Radiation; Radiation therapy; Radio; Radioisotopes; Radiolabeled; Radionuclide Imaging; Radionuclide therapy; Relative (related person); Renal clearance function; Reporting; Running; SLC2A1 gene; Serum; Small Business Innovation Research Grant; Solutions; Targeted Radiotherapy; Toxicology; Tracer; Translations; United States; Up-Regulation; Validation; X-Ray Computed Tomography; base; commercialization; cost; dosimetry; effective therapy; enzyme activity; experience; falls; glucose metabolism; hexokinase; image guided therapy; improved; in vivo; innovation; melanoma; novel; oncology; public health relevance; radiochemical; radiotracer; single photon emission computed tomography; theranostics; treatment planning; tumor

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.

描述（由申请人提供）：美国癌症协会报告说，在过去的30年里，黑色素瘤的死亡率在美国一直在上升。它是30岁以下人群中最常见的癌症之一，也是25至29岁成人中最常见的癌症。被认为是新疗法的潜在靶点的转移性黑素瘤细胞的一个特征是它们的葡萄糖代谢升高-以及伴随的葡萄糖转运蛋白（例如，GLUT 1）和己糖激酶活性。放射性标记的葡萄糖（即，[18 F]-FDG）多年来一直是转移性黑色素瘤成像的主要方法。没有可用的药物可以检测黑色素瘤代谢的差异，并可用于成像和靶向放疗。该提案的重点是开发、验证和商业化新型治疗诊断[203/212] Pb标记的葡萄糖胺缀合物（RMX-GC），用于转移性黑色素瘤的靶向成像和图像引导治疗。我们的创新方法采用了配对同位素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-alpha粒子治疗。[203 Pb/212 Pb]也是有吸引力的，因为203 Pb的半衰期相对较长（51 h），这有利于放射性示踪剂的集中制造，而212 Pb的半衰期为10 h，可以通过区域治疗中心进行商业化。RadioMeetings Inc.与ViewPoint Molecular Targeting LLC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203 Pb-RMX-GC进行详细评估，然后对放射性示踪剂212 Pb-RMX-GC进行验证。 我们的总体目标是为转移性黑色素瘤开发有效的治疗诊断方法，改善黑色素瘤的诊断和临床结局，副作用比目前的治疗方法更少-更轻。为实现这些目标，我们提出以下具体目标：1.开展并优化了203 Pb DOTA-氨基葡萄糖的放射性合成; 2.确定203 Pb DOTA-葡糖胺在荷黑色素瘤小鼠中的体内药效学; 3.记录203 Pb-DOTA-RMX-GC试剂盒的生产和质量控制方案，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，我们期望证明使用203 Pb/212 Pb-RMX-GC试剂用于成像以及随后用于转移性黑素瘤的图像引导治疗的可行性。这些结果将支持我们在IND申请和未来II期SBIR申请的规模化生产和毒理学研究方面的进一步投资。