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 low (e.g. beta) or high (e.g. alpha) linear energy transfer particles which cause single and double DNA strand breaks,leadingto cell death. Moreover, by switching the therapeutic radioisotope for one used in medical imaging, we can select tumours with high antigen expression prior to therapy and monitor therapeutic efficacy during and after the course of treatment.Together, we will develop novel xCT therapies for the precision treatment of lung cancer.

Hypothesis: xCT theranosticswill accumulate in drug-resistant tumours at high levels, eliciting a potent anti-tumour response. Our theranostic compounds designed and synthesised in WP1 will be used for the effective visualisation of drug resistant lungcancer in vivousing time course PET imaging. Subsequently, our xCT-targeting theranostics bearing the therapeutic Lu-177isotope will be used to selectively kill drug-resistant lung cancer due to their elevated expression of xCT. The beta-emitting Lu-177radiotherapeutic will delivera radiation payload to the tumour and the tumour microenvironment, resulting in ROS production, DNA damage, and ultimately cell death. Surviving cancer cells able to restore cellular redox homeostasis are likely to employ mechanisms that further elevate xCT expression. Upregulation of xCT will subsequently increase the amount therapeutic internalised by the cell, creating a positive feedback loop, delivering higher payloads of our theranostic to those tumours that are resistant to therapy. These studies will employ orthotopic models of lung cancer to measure accumulation of the theranostics at the tumour and to evaluate their efficacy for the treatment of drug resistant lung cancer. Importantly, preliminary work has shown that small molecule xCT radiotracersaccumulates in a xenograft model of drug resistant lung cancer at high levels, with low accumulation observed in all other healthy organs (large therapeutic index)