The Clemons laboratory incorporates fundamental cancer biology research, pre-clinical development of innovative therapeutic strategies and translational research, with a focus on upper gastrointestinal cancers.
Our research integrates novel in vitro and in vivo models to investigate functionally important drivers of tumour development and progression, and test new therapies for these cancers.
Broad vision and overview
Upper gastrointestinal cancers are one of the most common causes of cancer-related deaths worldwide. Patients frequently present with advanced metastatic disease, and resistance to standard chemotherapy is common, leading to poor survival rates for these diseases. Therefore, there is an urgent and unmet need for new therapies for upper gastrointestinal cancers. Our laboratory has developed pre-clinical models of oesophageal and gastro-oesophageal cancer to address important, clinically relevant questions, including how these cancers develop and progress from the very earliest stages through to invasive disease, and how we can therapeutically target different stages of the disease. We work collaboratively with the Phillips Laboratory and in partnership with clinicians in Cancer Surgery and Medical Oncology to translate our research into the clinic.
Novel therapies for upper gastrointestinal cancers
Oesophageal cancer has one of the highest rates of TP53 mutations (around 70 to 90 per cent of cases), which frequently leads to accumulation of the mutant p53 protein. We have demonstrated that the first-in-class drug APR-246 (ApreaAB, Sweden), which reactivates wild-type function to mutant p53 protein, effectively inhibits tumour growth, induces apoptosis and restores sensitivity to chemotherapy in oesophageal and gastric cancer pre-clinical models. This led to a phase II clinical trial of APR-246 in chemoresistant oesophageal and gastro-oesophageal junctional tumours across five hospitals in Melbourne, supported by the Victorian Cancer Agency.
Our current laboratory research is establishing predictive biomarkers and identifying the best combination therapies to partner with APR-246 and maximise its activity. The outcome of this research has the potential to improve outcomes for many different cancers, not just oesophageal cancer.
Functional drivers of oesophageal tumourigenesis
Oesophageal adenocarcinoma develops over time from Barrett’s oesophagus, an intestinal metaplasia of the distal oesophagus that arises as a consequence of chronic reflux. However, the functional drivers of metaplasia and progression to cancer at the molecular level are largely undefined. We are utilising CRISPR mediated genome editing and single cell RNA sequencing (Perturb-Seq) in pre-clinical models we have developed to systematically functionally characterise the drivers of oesophageal tumourigenesis, with the view to identifying novel opportunities for therapeutic intervention.
Janmaat VT, Nesteruk K, Spaander MCW, Verhaar AP, Yu B, Silva RA, Phillips WA, Magierowski M, van de Winkel A, Stadler HS, Sandoval-Guzmán T, van der Laan LJW, Kuipers EJ, Smits R, Bruno MJ, Fuhler GM, Clemons NJ, Peppelenbosch MP (2021). HOXA13 in etiology and oncogenic potential of Barrett's esophagus. Nat Commun. 7;12(1):3354.
Gotovac JR, Kader T, Milne JV, Fujihara KM, Lara-Gonzalez LE, Gorringe KL, Kalimuthu SN, Jayawardana MW, Duong CP, Phillips WA, Clemons NJ (2021). Loss of SMAD4 Is Sufficient to Promote Tumorigenesis in a Model of Dysplastic Barrett's Esophagus. Cell Mol Gastroenterol Hepatol. 12(2):689-713.
Fujihara KM, Corrales Benitez M, Cabalag CS, Zhang BZ, Ko HS, Liu DS, Simpson KJ, Haupt Y, Lipton L, Haupt S, Phillips WA, Clemons NJ (2021). SLC7A11 Is a Superior Determinant of APR-246 (Eprenetapopt) Response than TP53 Mutation Status. Mol Cancer Ther. 20(10):1858-1867.
Ceder S, Eriksson SE, Cheteh EH, Dawar S, Corrales Benitez M, Bykov VJN, Fujihara KM, Grandin M, Li X, Ramm S, Behrenbruch C, Simpson KJ, Hollande F, Abrahmsen L, Clemons NJ, Wiman KG (2021). A thiol-bound drug reservoir enhances APR-246-induced mutant p53 tumor cell death. EMBO Mol Med. 13(2):e10852.
Gotovac JR, Liu DS, Yates MJ, Milne JV, Macpherson AA, Simpson KJ, Eslick GD, Mitchell C, Duong CP, Phillips WA, Clemons NJ (2020). GRB7 is an oncogenic driver and potential therapeutic target in oesophageal adenocarcinoma. J Pathol. 252(3):317-329.
Liu DS, Duong CP, Haupt S, Montgomery KG, House CM, Azar WJ, Pearson HB, 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. Nat Commun. 8:14844.
Read M, Liu D, Duong CP, Cullinane C, Murray WK, Fennell CM, Shortt J, Westerman D, Burton P, Clemons NJ*, Phillips WA* (2016). Intramuscular Transplantation Improves Engraftment Rates for Esophageal Patient-Derived Tumor Xenografts. Ann Surg Oncol. 23(1):305-11. (*Co-senior author)
Liu DS, 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 tumour growth and overcomes chemoresistance in preclinical models of oesophageal adenocarcinoma. Gut. 64(10):1506-16. (*Co-senior author)