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.
Public Health Relevance Statement: Public Health Relevance: This proposal is focused on validation of a novel radiolabeled [203/212Pb] -glucosamine conjugates for targeted imaging and image guided therapy of metastatic melanoma. No other agents are available that provide theranostic approach for metastatic melanoma cancers.
Project Terms: Adult; Adverse effects; Age; Alpha Particles; American Cancer Society; base; Biodistribution; Businesses; Cancerous; Cell Therapy; Cells; Characteristics; Chemicals; Clinic; Clinical; Clinical Trials; commercialization; cost; Coupling; Cyclic GMP; Data; Death Rate; Development; Diagnosis; Diagnostic; Diagnostic Imaging; Disease; Documentation; Dose; dosimetry; Drug Formulations; effective therapy; enzyme activity; Evaluation; Excretory function; experience; falls; Funding; Future; Glucosamine; Glucose; glucose metabolism; Glucose Transporter; Half-Life; hexokinase; Image; image guided therapy; improved; in vivo; Incidence; innovation; Investments; Isotopes; Kidney; Knowledge; Label; Lead; Life Expectancy; Maintenance; Malignant Neoplasms; Manufacturer Name; Marketing; Medical Imaging; melanoma; Melanoma Cell; Metabolism; Metastatic Melanoma; Molecular Target; Mus; Non-Malignant; Normal Cell; novel; Nuclear; oncology; 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; public health relevance; Published Comment; Qualifying; Quality Control; Quality of life; Radiation; Radiation therapy; Radio; radiochemical; Radioisotopes; Radiolabeled; Radionuclide Imaging; Radionuclide therapy; radiotracer; Relative (related person); Renal clearance function; Reporting; Running; Serum; SLC2A1 gene; Small Business Innovation Research Grant; Solutions; Targeted Radiotherapy; theranostics; Tomography, Emission-Computed, Single-Photon; Toxicology; Tracer; Translations; treatment planning; tumor; United States; Up-Regulation (Physiology); Validation
