Molecular elucidation of Pl-3K/mTor pathway as a therapeutic target in inflammation-associated (gastrointestinal) cancers

Project Description

Inflammation-associated tumour promotion is a long-lasting process that, up to a point, can be reversed by therapeutic interference. Tumour promotion depends on the interaction of neoplastic cells with the microenvironment where excessive abundance of inflammatory mediators of the interleukin (IL-) 6/gp130 family promotes their expansion.

Although we established that genetic interference with Stat3 suppresses tumour promotion in our preclinical validated gp130F/F mouse model, Stat3 is a notoriously difficult molecule for therapeutic targeting. Surprisingly, we observed that administration of an mTor inhibitor reduced tumour burden, which at all stages remained dependent on PI3K/mTor signaling. We propose to:

  1. Define the molecular mechanisms leading to PI3K/mTor pathway activation. 
  2. Target of the PI3K/mTor pathway in inflammation-associated gastric tumourigenesis.
  3. Establish correlations between excessive STAT3 and mTOR signaling in human gastric cancer.
  4. Validate in other IL6/gp130 inflammation-linked cancers in mice (i.e. colon, liver) the therapeutic benefit of targeting the PI3K/mTor pathway,  and
  5. Identify network components which are selectively sensitized in tumour cells with excessive gp130 signaling as a means of identifying novel therapeutic targets.

The broad experimental expertise of the CIs with these models, the availability of the mouse strains and the proprietary small molecules ensures feasibility of these studies.

Collectively, these studies will highlight therapeutic opportunities for existing treatment modalities for inflammation-associated cancer for which there is currently limited availability of compounds that target non-redundant signalling components of the gp130/Stat3 network.

Lay Report:

Year

2012-2014

Researchers

Dr Michael Buchert, A/Prof Matthias Ernst

Funding Body

Cancer Council Research Grant

Institution

Ludwig Institute for Cancer Research (Jan-Sept 2012) Walter and Eliza Hall Institute of Medical Research (Oct 2012-Dec 2014)

Funding

$100,000 in 2012, $97,184 pa in 2013 & 2014

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