Oral Presentation 6th Australian Health and Medical Research Congress 2012

Therapeutic interference with mTorc1 restricts inflammation-associated and Stat3-dependent gastrointestinal tumourigenesis (#150)

Matthias Ernst 1 , Michael Buchert , Tracy Putoczki , Stefan Thiem
  1. Ludwig Institute for Cancer Research, Parkville, VIC, Australia

Gp130 receptor engagement on neoplastic cells by IL6-family cytokines provides a link by which the inflammatory microenvironment facilitates tumour promotion. Although excessive activation of the gp130-dependent Stat3 signaling node is commonly observed in solid tumours, Stat3 remains a challenging therapeutic target.
We mimicked excessive Stat3 signalling in gp130F/F mice as a molecularly validated preclinical model for inflammation associated intestinal-type gastric cancer [1], with aberrant mammalian target of rapamycin (mTor) pathway activity as a prominent shared feature. Therapeutic administration of the mTorc1 inhibitor RAD001 reversibly reduced gastric tumour burden in gp130F/F mice and suppressed colitis-associated cancer in wild-type mice. Similarly, prophylactic RAD001 treatment delayed onset of tumourigenesis in these models. Surprisingly, gp130-dendent PI3K/mTor activation occurred independently of Stat3 activation. Likewise, tumours from RAD001-treated mice still showed excessive Stat3 activation, even though genetic or pharmacological restriction of Stat3 activity limited the formation of gastric tumours in gp130F/F mice and of colitis-associated cancer in wild-type mice [1,2]. Consistent with our surprising finding that the readily drugable PI3K/Akt/mTorc1 pathway becomes rate-limiting for fast proliferating neoplastic cells, which are fuelled by excessive Stat3 activity, compound gp130F/F;Pten+/- mice show excessive gastric tumour burden.
We propose that “rapalogues” and related dual PI3K inhibitors target an “Achilles” heel that is common to many inflammation-associated malignancies, and that the gp130F/F mouse affords an autochthonous model for tumour progression to explore efficacy of novel orthogonal combination therapies with PI3K/mTor inhibitors.

1 Ernst et al, J Clin Invest 2008
2 Bollrath et al, Cancer Cell 2009