Dissecting the NeuroEndocrine Landscape of Extra-Pulmonary NeuroEndocrine Carcinoma to Discover Biomarkers with Clinical Utility

Abstract

Extra-pulmonary NeuroEndocrine Carcinomas (EP-NECs) are rare yet lethal cancers with limited treatment options. Although treated as a single entity, they are genomically and clinically heterogenous. There is an urgent need for tools to improve understanding of EP-NEC biology, optimise patient management, and identify more effective and personalised treatments. EP-NECs are histo-pathologically similar to Small Cell Lung Cancer (SCLC), a more common and better characterised NEC that originates from the lung. In this PhD thesis, I hypothesised that blood-based technologies that have proven relevant for SCLC could support biomarker discovery and enable development of preclinical models for EP-NECs. I demonstrated that CellSearch-CTCs are prevalent and quantifiable in EP-NEC patients, and could have prognostic utility. However, their overall low abundance hampers further validation of their clinical application. This also points towards divergent biology between EP-NECs and SCLC that potentially impacts patient management, since these cancers are currently treated similarly. For the first time, I demonstrated the feasibility of methylation-based ctDNA analysis in patients with EP-NEC by applying the T7-MBD-Seq method developed and optimised for SCLC in the CRUK Cancer Biomarker Centre. With further refinement, this approach holds potential as a highly sensitive biomarker platform for EP-NEC detection and classification, with scope to expand its application to the wider family of NeuroEndocrine Neoplasms (NENs). Finally, I established a CTC-Derived eXplant (CDX) model from a patient initially diagnosed with a NEC of unknown primary origin. This model was faithful in histopathology, molecular features and treatment sensitivity to the donor tumour. The CDX model led to the reclassification of the original patient diagnosis to a Merkel Cell Carcinoma (MCC). This opens the opportunity of immunotherapy for the donor patient, who is still alive, and would not have received this treatment with their original diagnosis. Remarkably, therefore, this CDX has potential to act as a patient avatar. Molecular profiling and ex vivo medium-throughput drug screening of this CDX have identified multiple additional patient-specific treatment sensitivities, that will be validated as part of future work, and may lead to further therapeutic opportunities for the donor patient. In conclusion, this study has generated pilot data supporting further development of cfDNA methylation profiling in patients with EP-NEC and other NENs. It has also shown that, where feasible, the CDX platform can guide individualised patient treatment (if the donor is still alive).

Date of Award	15 Jan 2024
Original language	English
Awarding Institution	The University of Manchester
Supervisor	Caroline Dive (Main Supervisor), Juan Valle (Co Supervisor) & Mairead Mcnamara (Co Supervisor)