Northern Institute for Cancer Research

Target Validation

Target Validation

About

The identification of novel targets for cancer treatment is one of the most challenging phases of drug discovery.

Research Leader

Steve Wedge 

About

We manipulate targets or an associated signaling pathway in human tumour cells by genetic (siRNA, shRNA, CRISPR/Cas9) or pharmacological methods. 

We also use complementary molecular strategies to mutate target proteins. This is to affect their function or directly inhibit their catalytic activity.

Putative targets undergo significant validation before being nominated as a drug discovery project. 

One of our scientists looking down a microscope

Our research

Target dependency

We determine the magnitude of effect inhibition of a target has on a tumour cell phenotype (eg proliferation or survival). 

We use bioinformatic approaches to examine target mRNA expression across patient tumour samples and cell lines. 

We examine target modulation  experimentally in multiple human tumour cell lines. These are selected on the basis of target expression, additional molecular pathology and histology.

We aim to determine the patient population that is likely to benefit most from treatment. 

We also seek data relevant to the role of the target in normal physiology. This provides an insight into how well tolerated a small molecule inhibitor is likely to be.

Target tractability

We assess a variety of parameters including the ability to:

  • make target protein
  • perform crystallography 
  • develop biophysical and cellular assays

Target novelty

We evaluate precedents for target inhibition by small molecules. We aim to tackle currently 'undrugged' targets or projects that use a structurally-enabled approach to achieve a differentiated inhibitor with distinct advantages.

Collaboration

We also do collaborative work on novel target hypotheses with academic and industry partners. We're open to discussing potential opportunities at an early stage.

Staining of tumour sample from a microscope

Projects and publications

Lochhead PA, Clark J, Wang LZ, Gilmour L, Squires M, Gilley R, Foxton C, Newell DR, Wedge SR and Cook SJ. (2016). Tumor cells with KRAS or BRAF mutations or ERK5/MAPK7 amplification are not addicted to ERK5 activity for cell proliferation. Cell Cycle.

O'Neill D, Jones D, Wade M, Grey J, Nakjang S, Guo W, Cork D, Davies BR, Wedge SR, Robson CN, Gaughan L. (2015). Development and exploitation of a novel mutant androgen receptor modeling strategy to identify new targets for advanced prostate cancer therapy. Oncotarget. [Epub ahead of print]

Staff

Staff

Steve Wedge

Alessio Ianetti
Suzanne Kyle
Sirintra Nakjang
Nicole Phillips
Huw Thomas
Sue Tudhope
Regina Mora Vidal
Elaine Wilmore
Anita Wittner
Yan Zhao


Postgraduate students

Richard Noble
Catherine Willoughby