Poster Presentation 31st Lorne Cancer Conference 2019

Therapeutically targeting Myc in gastric cancer (#337)

Riley J Morrow 1 2 , Ashleigh Poh 1 2 , Robert O'Donoghue 1 2 , Matthias Ernst 1 2
  1. Olivia Newton-John Cancer Research Institute, Heidelberg, VIC, Australia
  2. La Trobe University, School of Cancer Medicine, Bundoora, VIC, Australia

Background:

Gastric cancer remains deadly due to a lack of effective therapeutic options and late diagnosis of disease [1]. Myc is well described as being critical for gastric tumour development and progression [2]. Various studies have confirmed the overexpression of Myc in primary gastric cancers [3]. Hyperactivation of inflammatory signalling cascades, including the Jak/Stat3, is crucial for gastric cancer development and can cause the overexpression of Myc [4,5], however its pro-tumourigeneic role in this setting remains poorly understood.

Aim:

Previous findings from our lab using the Gp130FF mouse model, which spontaneously develop gastric adenomas through IL-11 dependent hyperactivation of Stat3, identified that Myc expression is significantly raised within these tumours. Further, systemic loss of a single Myc allele within this model significantly decreased tumour burden. Here, we investigate the cellular requirement for Myc in these gastric tumours by genetically reducing Myc specifically within epithelial cells. As well, we explore the therapeutic benefit of diminishing Myc transcriptional activity through the use of the small-molecule inhibitor IBET-151. 

Methods:

Tff1CreERT2;Mycflox;Gp130FF compound mutant mice were treated with tamoxifen and/or IBET-151 and stomachs collected. Tumour weight was recorded and tissues subjected to qRT-PCR, Western-blot, and immunohistochemical analysis to monitor the activation of Jak/Stat3 signalling.

Results:

A genetic reduction of Myc specifically within the gastric epithelium significantly reduced tumour growth, as well as activation of the Jak/Stat3 signalling pathway determined by a decrease in phosphorylated-Stat3. Therapeutic intervention with IBET-151 could also significantly reduce tumour growth, which was associated with a significant decrease in Myc mRNA expression, demonstrating its therapeutic benefit in this gastric cancer mouse model.    

Conclusion:

Our findings indicate that excessive Myc expression in the epithelial compartment may contribute to gastric cancer initiation and maintenance. Thus, Myc represents a promising therapeutic target for the treatment of gastric cancer.

  1. Fontana E and Smyth E.C (2016) Novel targets in the treatment of advanced gastric cancer: a perspective review, Therapeutic Advances in Medical Oncology, 8(2):113-125.
  2. Zheng L., Wang L., Ajani J and Xie K (2004) Molecular basis of gastric cancer development and progression, Gastric Cancer, 7(2):61-77.
  3. Calcagno D.Q., Leal M.F., Assumpcao P.P., Smith M.A and Burbano R.R (2008) MYC and gastric adenocarcinoma carcinogenesis, World Journal of Gastroenterology, 14(39):5962-5968.
  4. Ernst M., Najdovska M., Grail D., Lundgren-May T., Buchert M., Tye H., Matthews V.B., Armes J., Bhathal P.S., Hughes N.R., Marcusson E.G., Karras J.G., Na S., Sedgwick J.D., Hertzog P.J and Jenkins B.J (2008) STAT3 and STAT1 mediate IL-11-dependent and inflammation-associated gastric tumorigenesis in gp130 receptor mutant mice, The Journal of Clinical Investigation, 118(5):1727-38.
  5. Vervoorts J., Lüscher-Firzlaff J and Lüscher B (2006) The ins and outs of MYC regulation by posttranslational mechanisms, The Journal of Biological Chemistry, 281(46):34725-9.