February 23, 2023

Transcription-Factor Activity Profiling for the Enhancement of Personalised Treatments for Acute Myeloid Leukaemia

7th Call, iPostdoc

Short Summary

Inducible transcription factors are key points of control in many immune signalling pathways that drive cancer cell behaviour and drug resistance. This project seeks to better understand their role in the outcome of chemotherapy for blood cancer patients. We will do this by analysing patterns of gene expression in cancer patients from a previous PHRT-funded study, and also by developing a new imaging assay to find out how we can modulate transcription factor activity to improve drug efficacy.

Goals

The goal of this project is to explore the biological mechanisms that lie behind these differences in drug response. AML is a disease of the immune cells in our blood, and therefore we want to better understand the role that immune signalling plays in cancer treatment at the cellular level. We have chosen to analyse the activity of a set of transcription factors that lie at the heart of many signalling cascades, and drive the expression of genes that drive cancer growth and drug resistance. We will analyse patterns of transcription factor activity across the 34 AML patients, and see how this correlates with treatment response. We are also developing a high-content imaging assay that will allow us to measure the activation of these proteins at a single-cell level, and identify compounds that can positively influence their behaviour.

Significance

If we can understand how transcription factors affect drug response and resistance, we can better design targeted treatments for individual patients. By identifying compounds that modulate transcription factor activity, we hope also to identify potential new therapies, whether synthetic drugs or natural metabolites.

Background

Acute myeloid leukaemia (AML) is a rapidly progressing blood cancer. Without treatment, AML is fatal. With treatment, some patients can be completely cured, however others will face treatment failure and relapse. Finding the best available treatment for each patient is essential for improving the survival rate of this disease. The Snjider lab at ETH has pioneered a new technique called pharmacoscopy, where cancer cells taken from each patient are screened across a panel of nearly 100 drugs to find which are the most effective. A recent pharmacoscopy study in 34 AML patients in Switzerland has revealed that different patients can have very different drug response profiles, despite having a similar clinical diagnosis.