HYPOTHESIS

Developing novel methods for detecting interactions between STAT proteins and proposed inhibitors will allow for deconvolution of the STAT inhibitor landscape and further clarify the role of STAT proteins as inflammatory risk factors for cancer.

Background & Significance

Signal Transducer and Activator of Transcription (STAT) family proteins, especially STATs 1, 3 and 5 have been well-characterized with respect to their roles in cytokine signaling, inflammation and tumorigenesis47. This is especially prevalen within inflammatory conditions of the skin and in squamous cell carcinomas which have responded well to agents that block STAT signaling networks by targeting upstream kinases and receptors. While these types of ‘STAT signaling inhibitors’ continue to flood the scientific literature, the development of assays to determine if STAT inhibitors actually bind directly to STAT proteins are noticeably absent from the STAT signaling field48. Using a combination of modern chemical biology techniques, this project is focused on improving methodologies to characterize STAT inhibitors.

Objectives

This project aims to develop novel in vitro and in vivo methods to probe interactions between STAT proteins and inhibitors. These assays will be used to confirm or de-validate published STAT inhibitors by determining whether or not they actually bind to STAT proteins or whether they exert their effects via inhibition of other related (or unrelated) protein targets. In this project, the ESR will

optimize biophysical assays for detecting interactions between STATs and small molecule inhibitors;

assess mechanisms of action for known STAT inhibitors and identify novel targets within the STAT signaling pathway;

aid in the identification and optimization of novel STAT inhibitors;

explore the utility of STAT inhibitors in inflammation and cancer prevention.

Enrolment in Doctoral degree(s):

  • Karolinska Institute