Grant: Project Grant

Epidermal growth factor receptor I (EGFR) and II (HER2) are two proteins that are overexpressed in most solid tumors, making them prime therapeutic and imaging targets. In particular, 25 - 30% of all breast cancers overexpress HER2. EGFR is overexpressed in up to 90% of triple negative breast cancer (TNBC). About 15 - 20% of all breast cancers is TNBC. TNBC is very aggressive and is prevalent in younger women < 50 years of age. EGFR and HER2 consist of extracellular ligand binding and intracellular binding parts. The extracellular binding part consists of four sub-parts (termed domains 1 - IV) to which different molecules can specifically be bound. A combination of trastuzumab (targets domain IV) and pertuzumab (targets domain II) is approved for treating HER2 positive breast cancer but these only offer a small albeit significant improvement in outcome in patients. No approved therapies exists for EGFR positive TNBC. Our overall goal is to develop new radioactive drugs that simultaneously target different unique domains of EGFR and HER2 proteins. Radioimmunotherapy (radiolabeled antibodies) has shown promise in treating other cancers and many clinical trials are ongoing. Most radioimmunotherapy strategies have often given suboptimal results since these studies have focused on beta emitting radiation, which is less potent and tends to be toxic to adjacent healthy cells. In contrast, radioimmunotherapy based on alpha particles, such as actinium-225 (225Ac), are up to 1000-fold more effective. In this project, we will develop and test new compounds consisting of 225Ac-radiolabeled antibodies that target domains IV and II of HER2, and domains II and III of EGFR. These compounds will be tested in mouse models of HER2 and EGFR positive breast cancers. We anticipate that these strategies will be more effective than current treatment approaches in more than 50% of all BC. This work will support a potential clinical trial application for this population.