Targeted dual alpha therapy for disseminated cancer

Patients with late-stage cancers such as osteosarcoma, multiple myeloma and metastatic prostate and breast cancers that do not respond to available cancer therapies have a poor life quality and high mortality. In recent years, there has been increased interest in the use of radiopharmaceuticals, drugs containing radioisotopes, for the cancer diagnosis and treatment. Radionuclides decaying by the emission of alpha-particles have favorable properties (short range (<0.1 mm) and very high energy) for the treatment of circulating cancer cells and micrometastases (small clusters of cancer cells). Our goal is to develop novel alpha-emitting radiopharmaceuticals against skeletal and non-skeletal micrometastasis. A novel technology with potentially broad therapeutic applications for different cancers will be used. The treatment involves administration of a radiopharmaceutical solution containing the alpha-particle emitting radionuclide radium-224 and its daughter beta-particle emitting radionuclide lead-212 which is attached to a delivery vehicle. Antibodies or small molecule ligands are designed to bind to a unique antigen expressed by cancer cells, and will be used as lead-212 carriers. Lead-212 is a source of highly cytotoxic alpha particles via its decay to bismuth-212. Following injection of this solution: 1) Unbound natural bone-seeking radium-224 will target cancer cells in skeleton; 2) the complex with lead-212 will target the circulating cancer cells and micrometastasis in all parts of the body. For cancer patients, these new radiopharmaceuticals could potentially offer fewer side effects, reduce the need for hospitalizations, improved quality of life, increased productivity, and most importantly, extended lives.

The main goal of this research proposal is to achieve new knowledge, skills and methods that are going to be used in the development of novel radiopharmaceuticals for targeted alpha therapy for patients with disseminated multiple myeloma, osteosarcoma and breast cancer. This include the development and the preclinical testing of a novel and broad technology platform called DualAlpha. The novel radiopharmaceuticals comprise free uncomplexed bone-seeking Radium-224 (Ra-224), targeting the stromal elements and tumour-seeking lead-212 (Pb-212) complexed with a cancer cell surface-targeting monoclonal antibody (mAb). The aim is to destroy circulating tumour cells and micrometastases in the skeleton, bone marrow and in soft tissues and at the same time minimizing normal tissue radiotoxicity in patients with cancers associated with skeletal metastases including prostate cancer, breast cancer, osteosarcoma and multiple myeloma. A conjugated chelator with a mAb will be added to the Ra-224 solution in equilibrium with Pb-212 which makes Pb-212 complexed and hence, cancer-cell targeted. This new technology may enhance the overall tumor targeting of radiation dose and reduce toxicity by minimising uptake of Pb-212 in normal tissues and cells. The work plan of the PhD project is divided into three strongly interconnected parts to address the production, optimization and evaluation of the novel radiopharmaceuticals in vitro and in vivo. For patients the novel dual alpha targeted therapy is going to offer fewer side effects, less hospitalizations, improved quality of life, increased productivity, and most importantly, extended lives. The novel radiopharmaceuticals may be suitable for treating chemoresistant cancer metastases.