Research in the Phillips laboratory is focused on gastrointestinal cancers and has two major themes: Barrett’s oesophagus/oesophageal cancer and phosphoinositide 3-kinase mutations.
These themes are unified by the use of in vitro and in vivo models to address key issues in the biology and treatment of cancer and are supported by a broad skill base in cellular, molecular and translational biology.
Barrett’s oesophagus and oesophageal cancer
The Phillips laboratory has a major interest in the biology and pathogenesis of Barrett’s oesophagus and its progression to oesophageal adenocarcinoma (OAC). While Barrett’s oesophagus is benign, OAC has one of the lowest survival rates of all adult cancers, as the majority of patients with OAC present with late-stage disease, when prognosis is poor. Currently there are no clinical or histological parameters that allow clinicians to predict which patients will progress from Barrett’s oesophagus to OAC. There are also no treatments that completely reverse Barrett’s oesophagus or convincingly reduce a patient's predisposition to develop OAC, and only very limited therapeutic options for those patients that present with late-stage disease. One of the major impediments to developing new therapies for oesophageal cancer and/or identifying biomarkers of progression is the lack of good pre-clinical models in which to test hypotheses and new treatments.
In collaboration with the Clemons Laboratory, we are working to develop, test and translate new therapeutic strategies for oesophageal cancer. To facilitate this, we are developing novel patient-derived tumour xenograft (PDTX) models by growing human oesophageal biopsy material in immunodeficient models. The key objective of this work is to develop pre-clinical models of Barrett’s oesophagus and OAC that can be used to address important, clinically relevant questions, including how Barrett’s oesophagus develops, how it progresses to cancer and how we can therapeutically target different stages of the disease.
At a basic biology level, we are interested in the genetics of familial Barrett’s oesophagus/OAC and the signalling pathways driving the development and progression of Barrett’s oesophagus.
Phosphoinositide 3-kinase (PI3K) and cancer
The PI3K side of the laboratory is focused on understanding the biological consequences and clinical significance of PIK3CA mutations. Our unique transgenic model with a Cre-inducible Pik3ca mutation is an ideal system to investigate, both in vivo and in vitro, critical questions underlying the role, function and mechanism of action of Pik3ca mutations. We are also using this model to develop novel pre-clinical models. These will be used to explore the cellular and molecular basis for the development of resistance to PI3K pathway-targeted therapies and to trial potential new combination treatments. The primary focus of this work is colorectal cancer, but we are also applying this approach to other cancer types.
Liu, DS, Duong CP, Haupt S, Montgomery KG, House CM, Azar WJ, Pearson H, Fisher OM, Read M, Guerra GR, Haupt Y, Cullinane C, Wiman KG, Abrahmsen L, Phillips WA*, Clemons NJ* (2017). Inhibiting the system xC-/glutathione axis selectively targets cancers with mutant-p53 accumulation. Nature Commun. 8:14844.(*Co-senior Authors).
Liu DSH, Read M, Cullinane C, Azar WJ, Fennell CM, Montgomery KG, Haupt S, Haupt Y, Wiman KG, Duong CP, Clemons NJ*, Phillips WA* (2015). APR-246 potently inhibits tumor growth and overcomes chemoresistance in preclinical models of oesophageal adenocarcinoma. (*Co-senior Authors). Gut.64(10):1506-16.
Hare LM, Schwarz Q, Wiszniak S, Gurung R, Montgomery KG, Mitchell CA, Phillips WA. (2015). Heterozygous expression of the oncogenic Pik3caH1047R mutation during murine development results in fatal embryonic and extraembryonic defects. Dev Biol.404(1):14-26.
Kinross KM, Montgomery KG, Mangiafico SP, Hare LM, Kleinschmidt M, Bywater MJ, Poulton IJ, Vrahnas C, Henneicke H, Malaterre J, Waring PM, Cullinane C, Sims NA, McArthur GA, Andrikopoulos S, Phillips WA (2015). Ubiquitous expression of the Pik3caH1047R mutation promotes hypoglycemia, hypoinsulinemia and organomegaly. FASEB J.29(4):1426-34.
Hare LM, Phesse TJ, Waring PM, Montgomery KG, Kinross KM, Mills K, Roh V, Heath JK, Ramsay RG, Ernst M, Phillips WA (2014). Physiological expression of the PI3K-activating mutation Pik3caH1047R combines with Apc loss to promote development of invasive intestinal adenocarcinomas in mice. Biochem J.458(2):251-8.
Clemons NJ, Wang DH, Croagh D, Tikoo A, Fennell CM, Murone C, Scott AM, Watkins DN, Phillips WA (2012). Sox9 drives columnar differentiation of esophageal squamous epithelium: a possible role in the pathogenesis of Barrett’s esophagus. Am J Physiol Gastrointest Liver Physiol.303(12):G1335-46.
Kinross KM, Montgomery KG, Kleinschmidt M, Waring P, Ivetac I, Tikoo A, Saad M, Hare L, Roh V, Mantamadiotis T, Sheppard KE, Ryland GL, Campbell IG, Gorringe KL, Christensen JG, Cullinane C, Hicks RJ, Pearson RB, Johnstone RW, McArthur GA, Phillips WA (2012). An activating Pik3ca mutation coupled with Pten loss is sufficient to initiate ovarian tumorigenesis in mice. J Clin Invest.122(24):553-7.