The ASPIRE Path in Molecular Medicine

My research focuses on antibody-drug conjugates (ADCs) for HER2+ breast cancer. Although ADCs have revolutionized HER2+ breast cancer treatment, resistance is common (especially in metastatic patients). Moreover, we have limited knowledge of their mechanisms of action, resistance, and toxicity, as well as their interaction with the immune system. Furthermore, a translational gap exists between preclinical and clinical anti-HER2 ADC studies due to a paucity of preclinical models. This stems from the fact that trastuzumab, the backbone of both FDA-approved anti-HER2 ADCs (T-DM1 and T-DXd), does not bind to rodent Her2. To address this, I developed a tumor model containing a chimerized mouse/human Her2 receptor, which permits trastuzumab binding in immunocompetent models. Using this model, I am identifying mechanisms of resistance to T-DXd and will work to identify strategies to overcome it. I am also using this system to determine T-DXd’s effects on the tumor immune microenvironment and to investigate the efficacy of combinations with immunotherapy. Finally, we are collaborating with the VGER core to develop chimeric Her2-expressing transgenic mice, which will allow me to investigate the mechanisms of toxicity associated with T-DXd, particularly the high incidence of severe interstitial lung disease observed in patients.