The science behind the screening with Horizon Discovery

Infographic that shows cell pathways to DNA repair. Click to view full size.

Monday, 24 February 2014

I’m a member of AstraZeneca’s Oncology iMED strategy team, responsible for external project licensing and I am thrilled that we have recently signed our second deal with the Cambridge, UK-based biotech company Horizon Discovery (Horizon). This follows our announcement last year to license their HD-001 kinase programme which won the highly prestigious “Licensing Deal of the Year” accolade at the Scrip Awards 2013.

The latest deal is a collaboration and licence agreement with Horizon to jointly screen a range of oncology-relevant genotypes with the aim of identifying and validating novel drug targets that exhibit ‘synthetic lethality’ to these genotypes. We have focused the collaboration around some key tumour suppressor genes that have emerged from the human cancer genome data, as we believe these genes play critical roles in tumourigenesis. With Horizon’s expertise in gene editing and a proprietary siRNA functional screening platform, this collaboration strengthens our ability to screen against such targets.

So how will the project work? We’ve come up with a joint project plan with Horizon to ensure that innovation is leading the way.

First, human isogenic cell lines will be made to model the genetic anomalies found in cancer patients for siRNA screening. They are known as X-MAN™ (Gene-X, Mutant And Normal) cell lines, made by Horizon through adding or removing a target mutation in a parental cell to make a matched normal isogenic daughter cell line. In our case, this will be geared towards our selected tumour suppressor genes. This is particularly effective as these cell lines provide a clean system for screening.

Secondly, synthetic lethality screens will be run to identify putative target hits along with hit confirmation studies, using pre-agreed assay designs.

Finally, in-depth target validation will be carried out using a variety of techniques. This will include pathway analysis, confirmation of activity in endogenous cell lines and other functional assays to ensure that we have high confidence in the data.

The initial screens will include both functional endpoints and phenotypic endpoints to increase our chance of successfully identifying novel target opportunities.

The programme will focus on ‘synthetic lethality’, a concept whereby a combination of mutations in two genes leads to cell death, when neither mutation alone is lethal. The aim is to develop therapies that selectively cause synthetic lethality in cancer cells, sparing the normal cells.

An example of where this approach has been used before is with the development of PARP inhibitors for the treatment of cancers that harbour BRCA mutations. Cancers with these BRCA mutations have defects in homologous recombination (HR) and become more reliant on the PARP pathway to repair DNA damage. These cancers are therefore more sensitive to Parp inhibitors, which trigger cancer cell death, whereas normal cells remain viable as they have HR to fall back on to repair DNA damage.