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Defining the microbiome environment in patients with biliary tract cancer and its implications for therapy


Project Description

Biliary tract cancers (BTCs) encompass cancers of the extrahepatic/intrahepatic bile ducts, gallbladder and ampullary carcinoma. The only potentially curative option is surgical resection; median overall survival (OS) in the advanced setting: 11.7 months with cisplatin/gemcitabine chemotherapy1. BTC may develop through accumulation of genetic/epigenetic alterations; influenced by host immunity, diet, environmental/microbial exposure2. The human intestinal microbiome comprises ~1014 microorganisms that can influence host metabolism, immune system and cancer; the liver/biliary tract are exposed to gut microbiome via portal vein blood flow3. Diet, lifestyle, pharmacological factors (including antibiotics), and pro-/prebiotics can influence intestinal microbiota composition; microbial community imbalance (microbial dysbiosis) can potentiate hepatic steatosis and inflammation, and may promote liver tumour development. Additionally, the microbiome in bile may influence complications post BTC resection4. Furthermore, disruption of the microbiota impairs tumour response to immunotherapy and platinum chemotherapy in mouse tumours5. A better understanding of the role of microbes on BTC surgical outcomes is required, in addition to exploring their role in the efficacy of chemotherapy/immunotherapy in advanced BTC. This study will interrogate an institutional database including >600 patients with a BTC diagnosis for evidence of antibiotic use within 2 months before, or 1 month after, the first administration of platinum-based chemotherapy, and investigate the effects of their use on progression-free and OS. Cox regression analysis will elucidate any prognostic/predictive impact. Within prospective studies investigating (1) neoadjuvant cisplatin/gemcitabine versus upfront surgery in patients with resectable BTC and (2) the benefit of addition of immunotherapy to standard cisplatin/gemcitabine in advanced BTC, oral and gut microbiome samples will be collected at treatment initiation, with matched tumour biopsies/blood samples, when possible, to assess genomic alterations, as well as the density/phenotype of tumour infiltrating/circulating immune cell subsets. Metagenomic studies will examine the differences in the diversity/composition of the patient gut microbiome; correlated with surgical outcomes and tumour response.

Entry Requirements
This studentship is suitable for applicants with a Medical degree and Membership of The Royal College of Physicians (MRCP) or equivalent, who are pursuing a career in Medical Oncology and have an interest in gaining further experience in the field of biliary tract cancer research and clinical trials. Candidates should hold full General Medical Council [GMC] registration and International English Language Testing System (IELTS) (if appropriate) proficiency (at the time of commencing position).

For information on how to apply for this project, please visit the Faculty of Biology, Medicine and Health Doctoral Academy website (https://www.bmh.manchester.ac.uk/study/research/apply/). Applications will close when a suitable candidate is found so please apply as soon as possible.

Funding Notes

Fully funded two year MD supported through a Timpson Fellowship. Studentship to commence in September 2019 and covers tuition fees and salary. Salary will be on the Specialist Registrar scale, with starting salary within range £31,217 - £41,300 per annum, dependent on experience. If you are interested please make direct contact with the Supervisor to discuss the project. You MUST submit an online application form - choose MD Cancer Sciences.

As an equal opportunities institution we welcome applicants from all sections of the community regardless of gender, ethnicity, disability, sexual orientation and transgender status. All appointments are made on merit.

References

1. Valle J, Wasan H, Palmer DH et al. Cisplatin plus gemcitabine versus gemcitabine for biliary tract cancer. N Engl J Med 2010;362:1273-1281.

2. Nakamura H, Arai Y, Totoki Y et al. Genomic spectra of biliary tract cancer. Nat Genetics 2015;47:1003-1010.

3. Szabo G. Gut-liver axis in alcoholic liver disease. Gastroenterology 2015;148:30-36.

4. Spolverato G, Yakoob MY, Kim Y et al. Impact of complications on long-term survival after resection of intrahepatic cholangiocarcinoma. Cancer 2015;121:2730-2739.

5. Iida N, Dzutsev A, Stewart CA et al. Commensal bacteria control cancer response to therapy by modulating the tumor microenvironment. Science 2013;342:967-970.

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