Identification of subtype-specific biomarkers in small cell lung cancer

Although small cell lung cancer (SCLC) is a particularly aggressive disease, targeted therapies have remained largely unsuccessful and there were no major therapeutic advances in the last three decades. In the clinics, SCLC is still treated as a molecularly homogeneous malignancy. However, recent analyses led to the classification of neuroendocrine and molecular subtypes, defined by differential expression of four key transcription regulators: ASCL1, NEUROD1, POU2F3 and YAP1. Our study proposal aims to identify unique subtype-specific diagnostic and therapeutic biomarkers for SCLC patients with state-of-the-art multiomic approaches, and moreover to deepen our understanding of the biological and clinical significance of SCLC molecular subtypes. We intend to investigate the diagnostic and therapeutic significance of each subtype in a large panel of human SCLC cell lines in correlation with their proteomic and metabolomic profiles, in vivo metastatic capacity and sensitivity to potential targeted agents. Additionally, the specific features of the molecular subtypes will be also assessed by performing genetic mutation analyses and using in-depth machine-learning algorithms. All potential circulating biomarkers delineated by proteomics and metabolomics will be first validated by a series of in vivo experiments in different murine models. In addition, in order to improve patient selection and follow-up in a non-invasive manner, the specific PET-CT radiomic features of enrolled patients will be also analysed within the framework of the current study. Altogether, by identifying a wide range of novel biomarkers and potential therapeutic targets via multiomic approaches, the current study will possibly result in a new subtype-specific biomarker panel which will contribute to the development of individualized diagnostic and/or therapeutic strategies in this hard-to-treat disease.