Grant: Project Grant

Metastatic colorectal cancer (mCRC) is the second leading cause of death from cancer. At initial diagnosis almost half of patients have advanced disease and fewer than 10% live for more than five years. Surgery is the most effective treatment for controlling further spread, although local recurrence rates can range from 36-88%. A protein called epidermal growth factor receptor I (EGFR) has been shown to be increased in up to 80% of mCRC. Available drugs that target this protein are not effective. Another problem with treating patients with EGFR positive mCRC is that the current method for patient selection is less than optimal. Our goal is to develop more effective therapeutic and imaging agents that will improve the care of mCRC Radioimmunotherapy (i.e.radiolabeled antibodies ) have shown some promise in treating mCRC. However, current strategies have often given suboptimal results since all studies have focused on beta emitting radiation, which is less potent and tends to be toxic to adjacent healthy cells. In contrast, radioimmunotherapy strategies based on alpha particles, such as 225Ac, are up to 1000-fold more effective. Firstly, we propose to develop a set of novel therapeutic compounds which will be based on an antibody nimotuzumab (an antibody that specifically binds to EGFR protein on the cancer cell), linked to two other anticancer agents namely a drug and an alpha particle (actinium-225: 225Ac). The approach will be tested in cells and in mice bearing colorectal cancers. Secondly, we will develop an antibody imaging agent 89Zr-FABH that can be used together with PET/CT to more accurately diagnose and evaluate response to the new treatments against colorectal cancer. We anticipate that these strategies will be more effective than current treatment approaches for colorectal cancer and can be beneficial to other cancer types that express this protein - annually about 1 million new cases of EGFR-positive cancers are reported in North America.