Pharmacology and drug development

The aims of the Pharmacology & Drug Development Group (PDDG) are to optimise preclinical development and science-led clinical application of novel therapeutics and therapeutic strategies, focussing in particular on drug combination strategies for pancreatic cancer.  In the lab we use model systems representing pancreatic cancer and compare data generated with results from the analysis of samples from patients in clinical trials.  The PDDG is closely linked to the Early Phase Cancer Clinical Trials Team (EPCTT), led by Duncan Jodrell, and to clinical researchers at Cambridge University Hospitals Trust, supported by a team in the Cambridge Cancer Trials Centre.  This allows us to rapidly translate our laboratory discoveries into the clinic.

Pancreatic ductal adenocarcinoma (PDAC) remains relatively resistant to conventional chemotherapy and radiotherapy, contributing to the poor outcomes for patients diagnosed with this disease.  In addition, the successes seen in other tumour types associated with immunotherapy, have not translated into benefit for the vast majority of patients with PDAC.  Therefore, new therapeutic strategies are required, in a disease where only a small minority of patients are suitable for potentially curative resection at diagnosis.  Pancreatic cancer is one of the hard-to-treat cancers that is a key research priority for Cancer Research UK and the University of Cambridge Pancreatic Cancer Centre.

Causes for therapeutic resistance of PDAC have been targeted individually with modest efficacy.  Our principal hypothesis is that combination strategies will be required to achieve maximum clinical benefit, tackling multiple aspects of the biology of this disease.

In recent years we have developed new modelling approaches to support studies on gemcitabine and DNA Damage Response (DDR) inhibitors and interrogated, in depth, gemcitabine pharmacology.  We have developed software to aid evaluation of drug response (Combenefit and Dr Fit). We have investigated drug combinations with CHK1, Wee1 and ATR inhibitors (Koh, S.B. et al., 2018, Wallez Y. et al., 2018) and drugs that target signalling pathways downstream of mutant KRAS (collaboration with Simon Cook, Babraham Institute and Astra Zeneca).  As well as identifying combinations showing the greatest synergy in vitro, we optimise in vivo the scheduling of the therapeutic agents in a combination, to maximise efficacy and minimise normal tissue toxicity, in order to identify dosing regimens for translation into the clinic.  In collaboration with the MRC Trial Methodology Hub (Adrian Mander and colleagues) we use preclinical data and adaptive approaches to drive trial design.

We are also investigating methods to overcome the tumour microenvironment-driven resistance to immunotherapy, and are evaluating one such therapeutic approach in the clinic. Our aim now is to exploit our knowledge of DDR and tumour immunology in PDAC, to develop multi-modal combination therapy.