Kyra Fraser

Kyra Fraser Baseline PhD Plan

Many upper gastrointestinal (UGI) malignancies are associated with late-stage diagnosis and poor patient prognosis ​^1–3​. Pancreatic ductal adenocarcinoma (PDAC) is the most common type of pancreatic cancer and is particularly notorious for its high mortality rates; primarily due to the late onset of vague symptoms and aggressive nature of disease​⁴​. More than half of all patients are diagnosed at stage III or IV, at which point treatment options are extremely limited​^5,6​. Surgery is currently the only curative treatment available ​⁷​, however up to 85% of patients are identified as inoperable at the time of diagnosis due to the involvement of adjacent structures or the development of metastases​⁸​. Cholangiocarcinoma (CCA) is similarly afflicted, with late-stage presentation, diagnosis and limited treatment options all contributing to a five-year survival rate of just 5%​^9,​​³​.

With projections for pancreatic cancer to become the second leading cause of cancer-related deaths by 2030​¹⁰​, and the incidence of CCA also on the rise​¹¹​, it has never been more pertinent to focus research on early detection to improve treatment efficacy and reduce the burden of disease in high-risk patients.

Despite the increasing mortality rates, PDAC and CCA remain relatively rare, therefore widespread screening strategies within the asymptomatic general population would be impractical​⁴​. Instead, the focus must be on detecting malignancy in high-risk patients with familial history, health and lifestyle-related risk factors or symptoms suggestive of UGI disease. By defining high-risk and symptomatic patients with benign disease as the control population, biomarkers exclusively present or differentially expressed within a known cancer population may then be used to identify patients with early-stage malignancy.

Diagnostic tools that aid the early detection of PDAC and CCA must utilise samples readily available within primary care settings in order to be optimally successful. This research will therefore primarily focus on biomarker discovery and validation in blood samples due to their ease of accessibility and non-invasive nature. For my PhD project, human biological samples from the Accelerated Diagnosis of neuroEndocrine and Pancreatic TumourS (ADEPTS) biobank, as well as samples from new and existing collaborators will be used to facilitate this work.

This project seeks to identify biomarkers with potential utility to help diagnose early-stage PDAC and CCA within primary care. To do this, research will be focused on the following areas:

• Discovery of novel peripheral blood mononuclear cell (PBMC) and exosome-derived biomarkers
• Validation of promising biomarkers within a cohort of PDAC, CCA and high-risk or symptomatic patients

A systematic review of the literature will be undertaken to establish which published biomarkers show the most promise. Alongside this, work will be done to collate the findings of previous biomarker discovery research within the Pereira/Acedo lab.

Novel biomarker discovery will focus on the isolation and characterisation of exosomes and PBMCs of PDAC and CCA origin. Exosomes are extracellular vesicles present in virtually all biofluids and are vital for intercellular communication throughout the body​¹²​. Their involvement in the onset and progression of malignancy presents an intriguing opportunity for examination in the early detection of cancer​^13–15​. Work will initially focus on protocol optimisation and biomarker discovery in benign and malignant pancreatic and bile duct cell lines before progressing to patient serum samples. PBMCs are a population of immune cells which represent an additional rich source of biomarkers. These may also reveal expression profiles associated with early-stage malignancy and have shown promise throughout the published literature​^16–18​ The constituents and make-up of exosomes and PBMCs are wide ranging, therefore a multiomics approach will be taken when characterising cargo and composition changes. One such approach will use high-throughput proteomic techniques such as Olink; a platform capable of the measurement of over 5000 analytes, followed by the employment of machine-learning based algorithms to identify novel diagnostic signatures.

Carefully selected markers of interest from both the biomarker review and discovery arms of this project will then be taken forward for cross-validation in whole serum by ELISA or point of care devices. All promising biomarkers will ultimately be used in combination with findings from coinvestigators and collaborators within CanDetect to inform the generation of a multifaceted diagnostic platform for the early detection of UGI cancers in primary care.

References

​​1.          Coupland, V. H. et al. Incidence and survival of oesophageal and gastric cancer in England between 1998 and 2007, a population-based study. BMC Cancer 12, 1–10 (2012).

​2.          Coupland, V. H. et al. Incidence and survival for hepatic, pancreatic and biliary cancers in England between 1998 and 2007. Cancer Epidemiol 36, e207–e214 (2012).

​3.          Public Health England. Age Standardised Incidence Rates, One and Five-Year Survival, All Patients Diagnosed with Upper Gastrointestinal Cancers. http://www.ncin.org.uk/cancer_type_and_topic_specific_work/cancer_type_specific_work/upper_gi_cancers/ (2015).

​4.          Pereira, S. P. et al. Early detection of pancreatic cancer. Lancet Gastroenterol Hepatol 5, 698 (2020).

​5.          Mizrahi, J. D., Surana, R., Valle, J. W. & Shroff, R. T. Pancreatic cancer. The Lancet 395, 2008–2020 (2020).

​6.          CRUK Cancer Intelligence. Proportion of Cancer Cases by Stage at Diagnosis. https://crukcancerintelligence.shinyapps.io/EarlyDiagnosis/ (2020).

​7.          Brunner, M. et al. Current Clinical Strategies of Pancreatic Cancer Treatment and Open Molecular Questions. Int J Mol Sci 20, (2019).

​8.          Keane, M. G., Horsfall, L., Rait, G. & Pereira, S. P. A case–control study comparing the incidence of early symptoms in pancreatic and biliary tract cancer. BMJ Open 4, e005720 (2014).

​9.          Blechacz, B., Komuta, M., Roskams, T. & Gores, G. J. Clinical diagnosis and staging of cholangiocarcinoma. Nat. Rev. Gastroenterol. Hepatol 512, 512–522 (2011).

​10.        Rahib, L. et al. Projecting cancer incidence and deaths to 2030: The unexpected burden of thyroid, liver, and pancreas cancers in the united states. Cancer Res 74, 2913–2921 (2014).

​11.        Saha, S. K., Zhu, A. X., Fuchs, C. S. & Brooks, G. A. Forty-Year Trends in Cholangiocarcinoma Incidence in the U.S.: Intrahepatic Disease on the Rise. Oncologist 21, 594–599 (2016).

​12.        Zhou, B. et al. Application of exosomes as liquid biopsy in clinical diagnosis. Signal Transduction and Targeted Therapy 2020 5:1 5, 1–14 (2020).

​13.        Soung, Y. H., Ford, S., Zhang, V. & Chung, J. Exosomes in Cancer Diagnostics. Cancers (Basel) 9, (2017).

​14.        Arbelaiz, A. et al. Serum Extracellular Vesicles Contain Protein Biomarkers for Primary Sclerosing Cholangitis and Cholangiocarcinoma. HEPATOLOGY 66, 1125–1143 (2017).

​15.        Lapitz, A. et al. Liquid biopsy-based protein biomarkers for risk prediction, early diagnosis, and prognostication of cholangiocarcinoma. J Hepatol 79, 93–108 (2023).

​16.        Baine, M. J. et al. Differential gene expression analysis of peripheral blood mononuclear cells reveals novel test for early detection of pancreatic cancer. Cancer Biomarkers 11, 1–14 (2012).

​17.        Nichita, C. et al. A novel gene expression signature in peripheral blood mononuclear cells for early detection of colorectal cancer. Aliment Pharmacol Ther 39, 507–517 (2014).

​18.        Chen, S. et al. Identification of human peripheral blood monocyte gene markers for early screening of solid tumors. PLoS One 15, (2020).

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