Novel strategies to improve the effectiveness of radiation and targeted therapies in lung cancer

The majority of patients with cancer will receive radiotherapy at some time during the course of their treatment. The effectiveness of radiotherapy is dependent on the dose that can be delivered, but this is limited by normal tissue toxicity. In this programme of work, we aim to identify novel approaches to improve the effectiveness of radiation, while limiting the effects on normal tissue, with a focus on lung cancer.

Lung cancer is a devastating disease and the leading cause of cancer death worldwide. The most common form of lung cancer is non-small cell lung cancer (NSCLC) and patients with early stage disease can be treated with surgery or radiotherapy. However, most NSCLC patients present with locally advanced or metastatic disease. In these cases, chemotherapy, with or without radiotherapy, forms the cornerstone of treatment. Unfortunately, the prognosis remains poor for these patients, despite the development of novel therapies targeted to specific oncogenic drivers (e.g. EGFR, ALK, ROS, RET). Therefore, this programme aims to identify and evaluate novel therapies and targets for their potential to improve outcomes in lung cancer. The areas of focus for this programme are (i) improving the therapeutic margin of radiation by combining with drugs that either modulate the radiation-induced DNA damage response (DDR) or reduce radiation-induced lung toxicity (RILT), (ii) understanding the biological responses of normal cells in the lung when exposed to radiation alone or in combination with DDR inhibitors, (iii) identifying new targets to improve the effectiveness of radiation therapy, and (iv) identifying approaches for combining DDR inhibitors with targeted therapies (without radiation) for potential use in metastatic disease where chemotherapy (with or without combination with targeted therapies) forms the backbone of treatment. The development of DDR inhibitors has progressed rapidly since the demonstration that PARP inhibitors show clinical benefit in patients with BRCA1/2 mutated tumours. This has stimulated the development of inhibitors targeting other components of the DDR, including Ataxia Telangiectasia mutated (ATM) and Ataxia Telangiectasia and RAD3 related (ATR). DDR inhibition is an attractive strategy to improve the effectiveness of radiation, but there remains uncertainty about increased normal tissue toxicity and how to select which DDR approach to use in a particular setting. This program aims to clarify how different classes of DDR inhibitor affect tumour and normal lung tissue, and to identify the DDR approaches that have the potential for the greatest therapeutic margin in lung cancer.
Impact: This project will identify and characterise novel combination approaches for the use of DDR inhibitors in NSCLC patients with systemic/metastatic disease. This work will broaden the utility of DDR modulators from combinations with radiation and cytotoxic chemotherapy, to include combinations with cell signalling inhibitors which have greater potential for selective biological effects in tumour cells compared with normal tissues.