Programme(s) to which this project applies:
|☑ MPhil/PhD||☒ MRes[Med]||☒ URIS|
The mode of anaesthesia may have implications for cancer beyond the immediate post-operative period. A challenge in establishing consensus on best practice for anaesthetic technique in cancer surgery is that most clinical outcome data is based on a low level of evidence. The majority of research has been retrospective studies in heterogeneous patient cohorts. Histology, staging and patient co-morbidities all impact outcomes and are difficult to control. The interaction of anaesthetic agents and cancer cell survival and metabolism is complex. Different combinations of inhalational anaesthetic, intravenous anaesthetic (propofol), local anaesthetic and opioids formulate most anaesthetic plans for cancer surgeries.
Comprehensive genomic studies in gastric cancer have led to the identification of many new gastric cancer driver genes, as well as segregation of gastric cancer into several molecular subtypes, each with a unique combination of driver alterations. These studies described the main molecular subgroups, including 1) Epstein-Barr virus (EBV) characterized by DNA hypermethylation, ARID1A and PIK3CA mutations, 2) MSI (associated with increased mutation rates and hyper methylation, 3) Chromosomal instability (associated with high somatic copy number alterations (SCNA) and TP53 mutation), 4) Genomically stable tumours (characterized by low SCNA, RHOA mutations and CDH1), therefore illustrating the heterogeneity of GC. These studies and several other molecular studies primarily function as prognostic stratification tools, with the potential for predictive utility in gastric cancer. However, the challenges lie in understanding how each unique molecular subtype and driver alterations contribute to cancer development and their reliance on survival pathways that could translate into therapeutic opportunities.
Furthermore, we established novel paired GC and normal gastric tissue organoids from 34 patients, representative of the gastric cancer molecular subtypes described above. Our database encompasses comprehensive transcriptome, genomic and clinical information for each patient derived organoid. We also verified the possibility of carrying out a large-scale therapeutic drug sensitivity screen using these gastric organoids
Inhalational anaesthetics increase both Hypoxia Inducible Factor (HIF) and Insulin Growth Factor (IGF) which promote tumour cell growth, invasion and migration. In contrast, propofol appears to decrease HIF as well as having antioxidant and anti-inflammatory properties, making it preferable for the maintenance of anaesthesia for cancer operations. Results from several retrospective cohort analyses support this. Death was more likely for inhalation anaesthesia versus intravenous anaesthesia across all cancer surgeries (Hazard Ratio (HR) 1.46). Inhalation anaesthesia was associated with worse overall survival (HR 1.58) and worse recurrence-free survival (HR 1.42) in those undergoing esophagectomy. In mastectomy patients, intravenous anaesthesia had a significant reduction in recurrence (HR 0.55) . Survival for breast and colon cancer was higher at both 1 and 5 years, 4.7% and 5% respectively, for intravenous anaesthesia.
Our experimental design will comprise of utilizing the novel organoid models, described above, to comprehensively analyse the effect of anaesthetic drugs routinely used intraoperatively for patient induction on tumour organoids, ex vivo. We will then establish a multi-omic dataset by integrating anaesthetic treatment response ex vivo, patient demographics, survival outcomes, tumour sequencing and proteomic profile to determine potential markers that may determine the appropriate anaesthetic agent that will lead to more favourable patient outcomes. Our study will utilize a novel ex vivo culture system that will enable us to study the complex cellular function or tumour organoids and their interaction with anaesthetic agents.
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