Targeting purine and pyrimidine synthesis to treat Small Cell Lung Cancer

Small cell lung cancer is an aggressive and highly metastatic disease that represents around 15% of all lung cancer patients. The majority of patients (70%) present in the clinic with advanced disease that has spread beyond the lung. The treatment options available to these patients are limited to platinum-based chemotherapy. This is effective in the majority of patients, however almost all will rapidly relapse with platinum resistant disease. There is no effective second line therapies which has meant these patients have an appalling overall survival rate of 2-5% which has not improved over the past three decades. We have developed mouse models of platinum-resistant small cell lung cancer and performed extensive RNA-sequencing and metabolomics analysis on the primary tumour tissue from these animals which has revealed a dramatic increase in purine and pyrimidine synthesis. Importantly we have shown that inhibitors of these pathways kill small cell lung cancer cell lines. This project will take advantage of our mouse models of small cell lung to investigate the efficacy of these agents in vitro and in vivo as well as their capacity to kill primary or metastatic tumours or both.