LUNGOIDS

- Background, rationale: Lung cancer, with an overall 5-year survival rate below 20% is the leading cause of cancer-related mortality globally. Among lung cancer, non-small cell lung cancers (NSCLCs) are the most common group, with adenocarcinoma (ADC) and squamous cell carcinoma (SCC) being the two main histological phenotypes. Current therapies face substantial limitations due to insufficient clinical responses and the development of drug resistance. A thorough understanding of its tumour microenvironment (TME) is considered key to addressing these challenges, as the TME plays a pivotal role in disease progression and treatment efficacy.
- Hypothesis: We hypothesise that patient-derived preclinical models that encompass the specific characteristics of the NSCLC ADC and SCC subtypes will more accurately replicate patient tumour behaviour and responses than existing models. Thus, we propose to develop a platform of subtype-specific NSCLC patient-derived tumour organoids (PDTOs). This platform will also incorporate stromal and immune cells together with a human-specific artificial extracellular matrix (ECM), providing a close mimicry of the in vivo TME.
- Aims (primary and secondary): Our primary aim is to develop an advanced human-based NSCLC PDTO platform that reflects the unique tumour biology of ADC and SCC subtypes. Specifically, we aim to: 1) Rationally design and synthesise artificial ECMs based on biohybrid hydrogels capable of mimicking the physicochemical properties of human NSCLC tissues assisted by computational tools; 2) Develop and characterise ADC and SCC subtype-specific PDTOs within the tailored ECMs, incorporating immune and stromal elements, and study how the TME influences cancer progression; 3) Assess the functionality of the PDTOs as a testing platform using a novel combination therapy that integrates radio- and immunotherapy.
- Methods: We will integrate synthetic chemistry techniques with cell biology methods, assisted by computational tools (digital pathology and molecular modelling) to develop subtype-specific human-based NSCLC PDTOs. These models will be characterised and compared to parental tumours and gold-standard alternatives, through a multi-technique approach with last generation omics. Moreover, the functionality of the PDTOs as a platform to test combination therapies, consisting of radio-enhancing nanoparticles (NPs) and immune checkpoint inhibitors, will also be validated.
- Expected results and potential impact: Through the LUNGOIDS project, we aim to deliver a cutting-edge NSCLC PDTO platform that captures the tumour complexity of the ADC and SCC subtypes. By integrating subtype-specific human-based ECMs, together with specific immune and stromal components, we aim at offering a robust model to assess novel combination therapies and improve personalised treatments for NSCLC patients, ultimately improving patients’ outcomes.