Hepatic Models to personalise cancer chemotherapy

Description

The most commonly used chemotherapy regimens for colorectal cancer with liver metastases are oxaliplatin combined with 5-FU and leucovorin, i.e. FOLFOX, and irinotecan, 5-FU plus leucovorin, i.e. FOLFIRI.  These agents are typically administered over ~ 6 rounds of chemotherapy prior to surgery as neoadjuvant perioperative therapy, thereby making patients with borderline resectable tumours, or unresectable patients suitable for surgical intervention. However, these treatments can come with a cost to the patient due to toxicity, e.g. irinotecan-induced steatohepatitis, 5-FU-induced steatosis, and oxaliplatin-induced sinusoidal obstructive syndrome; this can require dose limitation, delays or even therapy cessation.  Collectively, this chemotherapy-associated liver injury (CALI) can adversely affect patient outcomes.  It is fairly common practice for another large group of patients to receive these chemotherapy treatments as adjuvant therapies post-operatively.  Similarly, a significant number of patients (~60%) will incur disease recurrence and will receive further chemotherapy.   Many of these latter two groups of patients who receive chemotherapy post-operatively (up to ⅓), will require dose or treatment adjustments because of toxicity.  Therefore, there are large numbers of patients within these three cohorts for whom the risk-versus-benefit balance for a specific chemotherapy regimen is not always clear.  This situation may have a serious impact on radiofrequency ablation or surgical resection treatments for some of these patients, and therefore affect overall patient outcomes, as well as overall quality of life.  Whilst there have been some reports describing potential mechanistic rationales for these drug-induced liver toxicities, in general we do not yet know why some patients are more prone to these ADRs, and therefore how we may better select a particular treatment regimen for a given patient. 

We will test the hypothesis that a platform of in vitro models, aligned with quantitative systems toxicology modelling, applied to patient liver specimens isolated during resection surgery for the patient cohort group who have disease recurrence, will enable the development of a risk:benefit score to discriminate between poor or positive therapeutic outcome for these patients – with likely benefits to the other patient groups. We propose to do this through the development of an integrated platform of patient-derived in vitro models that will be based on the collection of liver tissue (healthy and diseased) taken as surgical specimens – building on a 10 year collaboration with the surgical unit at LUFT. This PhD project will focus on one particular model, the hepatic organoid system, within a team of researchers using different primary human liver models (primary hepatocytes; liver organoids; precision-cut liver slices) and will allow the student to gain training in patient-derived models, advanced bioanalytical techniques (eg proteomics), and systems toxicology modelling, working in a dynamic, supportive and friendly team with established national and international academic and industrial collaborations.  This project will be co-supervised with colleagues in Pharmacology (Ian Copple, Sudeep Pushpakom and Amy Chadwick), and clinical colleagues (Dan Palmer, Rob Jones, Steve Fenwick), with whom we are building this patient-derived platform, as well as the Faculty-supported Human Liver Research Facility.

Research project related enquiries should be made in the first instance to Professor Chris Goldring chrissy@liv.ac.uk

To apply please send your CV and a covering letter to Professor Chris Goldring chrissy@liv.ac.uk