Exploiting the vulnerabilities of drug-resistant lung cancer with theranostics

Therapy resistance is one of the biggest problems currently facing clinical oncology. Despite a revolution in new anti-cancer therapies, such as check-point inhibitors and proton beam therapy, durable responses are often not observed due to acquired or innate resistance to existing treatments [1]. Through this project, we will develop an innovative preclinical programme of research to non-invasively detect and treat drug resistant lung cancer. There is an urgent need to develop new therapies for these patients; lung cancer is the most common cause of cancer death world-wide with ~1.6 million deaths/year and a ten-year survival rate of just 5% [2].

Deregulation of the tumour redox microenvironment drives therapy resistance

Biochemical antioxidant mechanisms play a critical role in development of acquired drug-resistance [3]. Central to the tumour antioxidant response is xCT, an amino acid transporter which is upregulated many-fold in drug-resistant lung cancer. xCT provides the rate-limiting precursors for glutathione biosynthesis, which is the body's most abundant antioxidant. We have built medical imaging tools to evaluate xCT activity in living subjects [4,5]. Importantly, using genetically engineered mouse models of lung cancer and in patient-derived tumour models we have used these tools to image xCT over-expression in drug-resistant cancer.

We will exploit the very mechanisms that cause existing treatments to fail using a therapeutic platform known as radioimmunotherapy. Radioimmunotherapy is an innovative approach, where an alpha or beta particle-emitting radionuclide is deliveredto the therapy-resistant tumours through antibody targeting, with minimal effect on normal healthy cells. Here, we will target xCT using a highly-specific human chimeric monoclonal antibody as our xCT-targeting agent (in collaboration with AgilVax, Inc.),tagged with a radionuclide. This radionuclide provides a radiation payload directly to the tumour through the emission of either...