Autotaxin Inhibitors for Treating Cancer

Background

The autotaxin (ATX) enzyme controls levels of lysophosphatidic acid (LPA), an important phospholipid involved in cell signalling which has been strongly linked to disease pathology characterised by abnormal cell migration. Modulation of ATX is likely to have a profound effect on lung disease progression including cancer growth and metastases and idiopathic pulmonary fibrosis (IPF).

Respiratory diseases have a significant socio-economic impact worldwide, with direct costs to the UK economy alone of over £6 billion, notwithstanding the significant morbidity rate of one in five associated with such diseases. A condition that is increasingly prevalent is IPF, a disease characterised by fibrotic tissue in the lung. IPF has exceptionally high mortality, with a median survival rate of approximately five years (compared with six years on average for cancer). Current estimates suggest that 5,000 new cases present annually in the UK, with a six-fold increase since 1979.

Lung cancer, in particular metastatic disease, is the leading cause of death globally with 1.59 million deaths in 2012 and projected to rise to 22 million in the next two decades. Despite metastatic disease having such a strong impact on both cancer patient survival and related healthcare costs, only a small percentage of the cancer research budget worldwide is dedicated to the treatment of metastasis.

Technology

Using knowledge of the protein structure, we developed novel lead chemical entities as potential inhibitors of ATX that formed the basis of a focussed compound library. This library has been assayed against recombinant human ATX using a synthetic substrate in an optimised spectrophotometric assay and activity confirmed using the natural substrate lysophosphatidylcholine (lysoPLC). A pattern (SAR) of promising ATX inhibitory activity, which is implicated in the pathogenesis of IPF and lung cancer metastasis, has emerged. 

We aim to develop cell-based assays to confirm the effect of these potential inhibitors of ATX. Firstly, in 2D monoculture, ATX release will be monitored in the presence and absence of the compounds using the natural substrate, lysoPLC, coupled to a fluorescent probe. Further to this, migration, in both lung cancer and IPF will be studied using a microfluidics technique incorporating 3D cell co-culture to create a more 'in vivo like' environment.

3D cell culture techniques have been optimised prior to implementing the microfluidics technique, and select compounds have demonstrated inhibition of migration in this culture system.

Key benefits

  • novel, tractable chemical entities with ATX inhibitory activity
  • a new 'in vivo like' model (tool) available to confirm inhibitors of migratory disease prior to in vivo testing

Markets & applications

  • potential novel entities against IPF and lung cancer metastatic disease
  • a reduction in in vivo testing due to prior evaluation in an 'in vivo like' microenvironment

Licensing & development

We are seeking partners for development. Please contact Debbie Stack for further information.