Project 462426

Radioactive atoms that emitting alpha-particles, so called alpha-emitters, are powerful weapons for late-stage cancer treatments. Those radionuclides can deposit a lot of energy in a short distance. When delivered specifically to the tumours, so called targeted alpha therapy, the radionuclides can destroy the cancer cells and spare the surrounding healthy tissues. Targeted alpha therapy with the radioactive atom actinium-225 has been used in clinical studies treating metastatic prostate cancers and has shown remarkable results in some patients that had previously exhausted other options. We intend to bring targeted alpha therapy for melanoma treatment. Melanoma is the main cause of death related to skin cancers and the incidents are steadily rising (over 40% in the past decade). Despite the recent advances in immune therapies, the survival for advanced melanoma is still low, with the 5-year-survival rate at 36%. There is need to develop additional systemic treatments for advanced melanoma. We plan to develop radiopharmaceuticals that can specifically carry powerful alpha-emitting payloads (bismuth-213, actinium-225 and thorium-227) to cancer cells. We will first design and discover the best molecules to carry each radioactive payload, which we will be using to prepare the radiopharmaceuticals. We will then evaluate the uptake of those radiopharmaceuticals in cells and the biodistribution in mice bearing melanoma xenografts, followed by using those radiopharmaceuticals to treat human melanoma in preclinical models. We will monitor if the treatments are effective, evaluate the toxicity, and develop an optimal treatment plan. The proposed project could lead to the discovery of novel radiopharmaceuticals that benefit patients with advanced melanoma.