Grant: Project Grant

Trastuzumab (Herceptin) is an effective drug for treatment of HER2-positive breast cancer that has spread to other organs in the body. However, this drug is not effective for treatment of breast cancer that has spread to the brain because it penetrates the brain in only limited amounts that are not sufficient for eradicating tumours. This is due to the blood-brain-barrier (BBB) which prevents trastuzumab from being taken up into the brain. In the proposed research, we plan to develop a more potent form of trastuzumab by linking the drug to a radioisotope, actinium-225 that emits a type of radiation called alpha particles that is very powerful for killing cancer cells. Trastuzumab will be further modified with peptides that allow it to cross the BBB and enter the brain. In addition, we will study a technique called MRI-guided focus ultrasound (MRgFUS) that applies ultrasound to the region of the brain where the tumour is located in order to disrupt the BBB and allow the actinium-225-linked trastuzumab to reach the brain metastasis. We will evaluate the uptake of the actinium-225-linked trastuzumab into HER2-positive human breast cancer tumours implanted into the brain in mice and estimate the radiation dose delivered to the tumour and normal organs. We will then determine the maximum amount of the actinium-225-linked trastuzumab that can be safely administered to mice. Finally, we will study treatment of the tumours in the brain of mice with the actinium-225-linked trastuzumab in combination with the MRgFUS. We will compare the effectiveness of this new treatment with the trastuzumab combined with MRgFUS, or to tucatinib, a new drug which has recently been approved for treatment of brain metastasis in patients with HER2-positive breast cancer.