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.
The Clemons laboratory is part of a national consortium of clinicians and researchers called PROBE-Net, the Progression of Barrett's Esophagus to Cancer Network, currently funded by an NHMRC Centre of Research Excellence grant.
Novel therapies for upper gastrointestinal cancers
The TP53 gene is mutated in over half of all cancers and is associated with tumourigenesis, resistance to chemotherapy and poor prognosis. 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 has 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 complementing this clinical trial by establishing predictive biomarkers and identifying the best combination therapies to partner with APR-246 and maximise its activity. These include treatments that enhance accumulation of p53 protein, such as MDM2 inhibitors and ionising radiation, and drugs that inhibit antioxidant production, which synergise with the recently identified glutathione inhibitory effects of APR-246. The outcome of this research has the potential to improve outcomes for many different cancers, not just oesophageal cancer.
Functional drivers of oesophageal tumourigenesis
The incidence of oesophageal adenocarcinoma, one of the two major subtypes of oesophageal cancer, is rising faster than any other solid malignancy worldwide. 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. Using novel in vivo tissue reconstitution models, xenograft models and transgenic models, we have established that reactivation of the hedgehog signalling pathway is an important driver of the metaplastic process. This now provides the rationale for exploring the potential of inhibitors of this pathway to prevent progression or even reverse metaplasia.
Our range of innovative in vivo models also allows us to determine the important functional genetic events that drive tumourigenesis in Barrett’s metaplasia. Recent next-generation genomic studies have defined stage-specific mutations to determine disease progression, including TP53 mutations in pre-invasive disease and SMAD4mutations or loss in invasive disease. Our research is defining the functional effects of these and other events, including the influence of the tumour stromal microenvironment in oesophageal tumourigenesis, with the view to identifying novel opportunities for therapeutic intervention.
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)
Wang DH, Tiwari A, Kim ME, Clemons NJ, Regmi NL, Hodges WA, Berman DM, Montgomery EA, Watkins DN, Zhang X, Zhang Q, Jie C, Spechler SJ, Souza RF (2014). Hedgehog signaling regulates FOXA2 in esophageal embryogenesis and Barrett's metaplasia. J Clin Invest. 124(9):3767-80.
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.
Wang DH, Clemons NJ, Miyashita T, Dupuy AJ, Zhang W, Szczepny A, Corcoran-Schwartz IM, Wilburn DL, Montgomery EA, Wang JS, Jenkins NA, Copeland NA, Harmon JW, Phillips WA, Watkins DN (2010). Aberrant epithelial-mesenchymal Hedgehog signaling characterizes Barrett's metaplasia. Gastroenterology. 138(5):1810-22.
Clemons NJ, Shannon NB, Abeyratne LR, Walker CE, Saadi A, O'Donovan ML, Lao-Sirieix PP, Fitzgerald RC (2010). Nitric oxide-mediated invasion in Barrett's high-grade dysplasia and adenocarcinoma. Carcinogenesis. 31(9):1669-75.
Clemons NJ, McColl KE, Fitzgerald RC (2007). Nitric oxide and acid induce double-strand DNA breaks in Barrett's esophagus carcinogenesis via distinct mechanisms. Gastroenterology. 133(4):1198-209.